Sealed containers and methods of filling and resealing same

ABSTRACT

A container and method for filling same. The container includes a penetrable and resealable portion that is resealable, and a container body having a sealed empty chamber in fluid communication with the penetrable and resealable portion for receiving therein a substance. The resealable member may be dome-shaped or have a convex outer surface. A method of filling the container includes penetrating the penetrable and resealable portion with an injection member and introducing a substance into the chamber, withdrawing the injection member, and resealing the penetration hole in the resealable member made by the injection member during penetration.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.14/610,016, filed Jan. 30, 2015, now U.S. Pat. No. 9,637,251, entitled“Sealed Containers and Methods of Filling and Refilling Same,” which isa continuation of U.S. patent application Ser. No. 13/193,662, filedJul. 29, 2011, now U.S. Pat. No. 8,960,242, entitled “Sealed Containersand Methods of Making and Filling Same,” which is a continuation ofsimilarly-titled U.S. patent application Ser. No. 12/791,629, filed Jun.1, 2010, now U.S. Pat. No. 7,992,597, which is a divisional ofsimilarly-titled U.S. patent application Ser. No. 11/515,162, filed Sep.1, 2006, now U.S. Pat. No. 7,726,352, which is a continuation ofsimilarly-titled U.S. patent application Ser. No. 10/655,455, filed Sep.3, 2003, now U.S. Pat. No. 7,100,646, which claims priority tosimilarly-titled U.S. Provisional Patent Application No. 60/408,068,filed Sep. 3, 2002 and is also a continuation-in-part of U.S. patentapplication Ser. No. 10/393,966, filed Mar. 21, 2003, entitled“Medicament Vial Having A Heat-Sealable Cap, And Apparatus and MethodFor Filling The Vial,” now U.S. Pat. No. 6,684,916, which is adivisional of similarly-titled U.S. patent application Ser. No.09/781,846, filed Feb. 12, 2001, now U.S. Pat. No. 6,604,561, issuedAug. 12, 2003, which, in turn, claims the benefit of similarly-titledU.S. Provisional Application Ser. No. 60/182,139, filed on Feb. 11,2000. The above-referenced applications are hereby expresslyincorporated by reference as part of the present disclosure.

FIELD OF THE INVENTION

The present invention relates to sealed containers, and moreparticularly, to containers, such as medicament vials, which have uniquespool-like or “diabolo” shaped configurations, and still moreparticularly, to containers that include a closure device thathermetically seals the container, that can be sterilized usingirradiation, such as laser, gamma, e-beam, x-ray or other forms ofionizing radiation, that can be needle filled when sealed to thecontainer, and that can be thermally resealed after needle filling, suchas by applying laser radiation to the needle fill hole.

BACKGROUND OF THE RELATED ART

Medicaments such as vaccines are often stored in vials prior to use.Vials typically include a main body portion that is either cylindricalor spherical in shape and has a neck portion depending therefrom. Theneck portion defines a mouth for receiving the medicament into aninterior chamber defined in the vial body. Normally, the vials arefilled with medicament, and then a pre-sterilized cap or closure deviceis installed to seal the medicament within the vial.

The vial cap is typically a two-piece assembly that includes a stopperand a securing ring. The stopper is inserted into the mouth of the vialand is configured to effectuate a circumferential seal. The securingring is engaged with the neck of the vial and at least partiallyoverlies the stopper so as to retain the stopper within the vial mouth.The stopper is made of vulcanized rubber or similar resilient materialthat neither contaminates nor affects the contained medicament.Vulcanized rubber has been determined to be a safe and effectivematerial for manufacturing vial caps for containing numerous types ofmedicaments. Vulcanized rubber, however, is infusible, and therefore anyneedle holes in such caps are not heat-resealable.

The securing ring is typically configured such that a portion of thestopper is exposed and can be accessed by a needle, thereby allowing themedicament to be withdrawn. Traditionally, securing rings are threadablyengaged with the vial or affixed therewith by a metal crimpingtechnique. In applications such as healthcare, a crimped metal securingring is frequently preferred, since a crimped ring provides a mechanismfor assuring that the vial has not been opened or compromised subsequentto being filled or sterilized.

Referring to FIG. 1, a prior art cap for a medicament vial is designatedgenerally by reference numeral 10. The cap 10 includes a vulcanizedrubber stopper 12, which is slidably received within the open end ormouth 8 of a cylindrical vial body 14. The vial body 14 is made of glassor like material, and it defines a chamber 16 for receiving medicament.An aluminum locking ring 18 surrounds the periphery of the stopper 12and vial 14, and is crimped in place to secure, connect and seal the cap10 to the vial body 14. The locking ring 18 includes a central aperturewhich affords limited access to the stopper 12.

In order to fill such prior art vials with a sterile fluid or othersubstance, such as a medicament, it is typically necessary to sterilizethe unassembled components of the vial, such as by autoclaving thecomponents and/or exposing the components to gamma radiation. Thesterilized components then must be filled and assembled in an asepticisolator of a sterile filling machine. In some cases, the sterilizedcomponents are contained within multiple sealed bags or other sterileenclosures for transportation to the sterile filling machine. In othercases, the sterilization equipment is located at the entry to thesterile filling machine. In a filling machine of this type, everycomponent is transferred sterile into the isolator, the storage chamberof the vial is filled with the fluid or other substance, the sterilizedstopper is assembled to the vial to plug the fill opening andhermetically seal the fluid or other substance in the vial, and then thecrimping ring is assembled to the vial to secure the stopper thereto.

One of the drawbacks associated with such prior art vials, and processesand equipment for filling such vials, is that the filling process istime consuming, and the processes and equipment are expensive. Further,the relatively complex nature of the filling processes and equipment canlead to more defectively filled vials than otherwise desired. Forexample, typically there are at least as many sources of failure asthere are components. In many cases, there are complex assembly machinesfor assembling the vials or other containers that are located within theaseptic area of the filling machine that must be maintained sterile.This type of machinery can be a significant source of unwantedparticles. Further, such isolators are required to maintain sterile airwithin a barrier enclosure. In closed barrier systems, convection flowis inevitable and thus laminar flow, or substantially laminar flow,cannot be achieved. When operation of an isolator is stopped, a mediafill test may have to be performed which can last for several, if notmany days, and can lead to repeated interruptions and significantreductions in production output for the pharmaceutical or other productmanufacturer that is using the equipment. In order to address suchproduction issues, government-imposed regulations are becomingincreasingly sophisticated and are further increasing the cost ofalready-expensive isolators and like filling equipment. On the otherhand, governmental price controls for injectables and vaccines,including, for example, preventative medicines, discourage such majorfinancial investments. Accordingly, there is a concern that fewercompanies will be able to afford such increasing levels of investment insterile filling machines, thus further reducing competition in theinjectable and vaccine marketplaces.

In order to address these and other concerns, the present inventor hasdetermined that it would be desirable to manufacture and fill vials byfirst assembling the stopper to the vial, sterilizing the assembledstopper and vial, such as by irradiation, and then filling the assembledvial by inserting a needle or like injection member through the stopperand introducing the medicament through the needle into the sterilizedvial. One problem encountered with this approach, however, is that whenthe needle or like injection member is inserted through the stopper andthen withdrawn, it leaves a tiny hole in the stopper. The material ofthe stopper is resilient in order to reduce the diameter of the hole,and therefore the hole is usually small enough to keep the medicamentfrom leaking out. However, the hole typically is not small enough toprevent air or other gases from passing through the hole and into thevial, and therefore such holes can allow the medicament to becomecontaminated or spoiled.

It has been a practice in the pharmaceutical fields to add preservativesto medicaments, such as vaccines, in order to prevent spoilage of themedicaments upon exposure to air or other possible contaminants. Certainpreservatives, however, have been determined to cause undesirableeffects on patients. Consequently, many medicaments, including vaccines,are preservative free. These preservative-free medicaments, andparticularly preservative-free vaccines, are subject to contaminationand/or spoilage if contained within a vial wherein the stopper has aneedle hole as described above.

As noted above, it is difficult to maintain the sterility of stoppersand vials during the transportation, storage and assembly process. Thereis a need, therefore, for vials and stoppers which can be assembled andthen sterilized as a unit prior to filling the vial assembly withmedicament. Although crimped metal rings provide a mechanism forensuring that the vial has not been compromised, the metal ring does notallow the vial assembly to be easily sterilized as a unit by using agamma sterilization technique or similar process. A metal ringcomplicates the gamma sterilization process. Due to the density of thematerial, shadows (i.e., areas where the gamma radiation is preventedfrom passing through the material) are created which reduces theassurance that the interior storage cavity has been completelysterilized. Also, the handling of the metal rings during the assemblyprocess can create dust and/or other particulates that can contaminatethe clean environment established for vial assembly and filling.

Additionally, the shape of conventional medicament vials can bedisadvantageous from a safety and/or handling perspective. For example,when a healthcare worker is withdrawing medicament from the vial,his/her fingers must grasp the cylindrical or spherical vial body. Inconventional vials, the vial body has an outer diameter that is greaterthan the outer diameter of the cap or closure. If the needle slips offof the cap due, for example, to the relative placement of the fingerswith respect to the cap, the healthcare worker's fingers are positionedin the slip path of the needle and therefore are likely to be pierced,causing a variety of safety concerns. In addition, such conventionalvials have a relatively high center of gravity making them prone totipping during handling, and further, define shapes and/orconfigurations that are not always well suited for needle filling and/orautomated handling in such needle filling and laser or other thermalresealing machines.

Accordingly, it is an object of the present invention to overcome one ormore of the above-described drawbacks and disadvantages of the priorart.

SUMMARY OF THE INVENTION

In accordance with a first aspect, the present invention is directed tomethod. The method comprises providing a container including a containerbody and a heat-resealable stopper fusible in response to theapplication of thermal energy thereto. The body defines an emptychamber, sealed with respect to ambient atmosphere, and in fluidcommunication with the stopper for receiving therein a predeterminedsubstance. The container further includes a base, a mid-portion, and anupper portion axially spaced from the base on an opposite side of themid-portion relative to the base, wherein each of the base and upperportion define a laterally-extending dimension greater than a maximumlaterally-extending dimension of the mid-portion. The method furthercomprises the steps of penetrating the stopper with an injection membercoupled in fluid communication with a source of predetermined substance,introducing the predetermined substance through the injection member andinto the chamber of the container, and withdrawing the injection memberfrom the stopper. Additionally, the method comprises the steps ofengaging the base of the body with a support during the step ofwithdrawing the injection member and substantially preventing axialmovement of the body relative thereto, and applying sufficient energy tothe stopper to thermally fuse the penetrated region and form asubstantially gas-tight seal between the penetrated region and thechamber.

In some embodiments, the method further comprises the step of assemblingthe stopper and container body robotically and over-molding atamper-resistant portion to the stopper and container body. In someembodiments, the assembly of the container body and stopper occurs priorto installing the container body/stopper assembly in a moldingapparatus.

Another aspect of the present invention is directed to a method. Themethod comprises forming a container body defining a chamber in a firstmold, which is performed in a clean room environment, and forming astopper in a second mold in the same clean room environment. The stopperis a thermoplastic stopper defining a needle penetration region that ispierceable with a needle to form a needle aperture therethrough, and isheat resealable to hermetically seal the needle aperture by applyinglaser radiation at a predetermined wavelength and power thereto. Themethod further comprises the step of assembling the stopper andcontainer body in the clean room environment to form a sealed emptycontainer. In some embodiments, the first and second molds are locatedside-by-side within the clean room environment.

In some embodiments, the method further comprising the steps of:penetrating the needle penetration region of the stopper with a fillingneedle such that the filling needle is in fluid communication with thechamber of the container, introducing the substance through the needleand into the chamber of the container, and withdrawing the fillingneedle from the stopper. Further, the method comprises the steps oftransmitting laser radiation at the predetermined wavelength and poweronto an aperture formed in the needle penetration region of the stopper,and hermetically sealing the aperture.

Another aspect of the present invention is directed to a method. Themethod comprises forming a sealed empty container within a mold. Thecontainer includes a body defining a sealed empty chamber, and athermoplastic portion in fluid communication with the body. Thethermoplastic portion defines a penetrable region that is penetrable bya filling member and is heat resealable to hermetically seal an aperturetherein by applying laser radiation at a predetermined wavelength andpower thereto. The method further comprises the steps of: penetratingthe penetrable region of the thermoplastic portion with a filling membersuch that the filling member is in fluid communication with the sealedempty chamber, introducing the substance through the filling member andinto the chamber, and withdrawing the filling member from thethermoplastic portion. Further, the method comprises the steps oftransmitting laser radiation at the predetermined wavelength and poweronto an aperture formed in the penetrable region of the thermoplasticportion, and hermetically sealing the aperture and the substance withinthe chamber. In some embodiments, the method further comprisessterilizing the sealed empty container between the forming andpenetrating steps.

Another aspect of the present disclosure is directed to a vial assemblyfor storing a substance, such as a medicament, comprising a bodydefining an opening, and a chamber in fluid communication with theopening for receiving therein the substance. The body defines a base, amid-portion, and an upper portion axially spaced from the base on anopposite side of the mid-portion relative to the base. Each of the baseand upper portion define a laterally-extending dimension that is greaterthan a maximum laterally-extending dimension of the mid-portion. In acurrently preferred embodiment of the present invention, each of thebase, mid-portion and upper portion are approximately circular in crosssection, and a maximum diameter of each of the base and upper portion isgreater than a maximum diameter of the mid-portion to thereby define anapproximate diabolo or spool shape. Preferably, the vial assemblyincludes a plastic tamper-resistant portion that is fixedly secured tothe body and extends at least partially over the stopper for preventingunnoticeable removal of the stopper.

In some embodiments, the stopper includes a heat resealable portionoverlying a substantially infusible portion. In another embodiment ofthe present invention, the stopper is a thermoplastic stopper defining aneedle penetration region that is pierceable with a needle to form aneedle aperture therethrough, and is heat resealable to hermeticallyseal the needle aperture by applying laser radiation at a predeterminedwavelength and power thereto. The stopper comprises a thermoplastic bodydefining (i) a predetermined wall thickness in an axial directionthereof, (ii) a predetermined color and opacity that substantiallyabsorbs the laser radiation at the predetermined wavelength andsubstantially prevents the passage of the radiation through thepredetermined wall thickness thereof, and (iii) a predetermined colorand opacity that causes the laser radiation at the predeterminedwavelength and power to hermetically seal a needle aperture formed inthe needle penetration region thereof in a predetermined time period ofless than approximately 2 seconds and substantially without burning theneedle penetration region.

Another aspect of the present disclosure is directed to a method. Themethod comprises providing a vial including a body defining an opening,a chamber in fluid communication with the opening for receiving thereina predetermined substance, a base, a mid-portion, and an upper portionaxially spaced from the base on an opposite side of the mid-portionrelative to the base. Each of the base and upper portion define alaterally-extending dimension greater than a maximum laterally-extendingdimension of the mid-portion, and a heat-resealable stopper fusible inresponse to the application of thermal energy thereto. Prior to fillingthe vial with substance, the method further comprises the step ofassembling the stopper and vial and forming a substantially gas-tightseal between the stopper and vial. The method further comprises thesteps of sterilizing the empty assembled stopper and vial and supportingthe vial with a vial support including a mounting surface in engagementwith the mid-portion of the vial, an upper surface located on one sideof the mounting surface, and a lower surface located on another side ofthe mounting surface. Further, the method comprises the steps ofpenetrating the stopper with a needle coupled in fluid communicationwith a source of predetermined substance, introducing the predeterminedsubstance through the needle and into the interior of the vial,withdrawing the needle from the stopper, and applying sufficient thermalenergy to the penetrated region of the stopper to fuse the penetratedregion and form a substantially gas-tight seal between the penetratedregion and the interior of the vial.

One advantage of the preferred embodiments of the present invention isthat the vial defines a diabolo or spool-like shape, thus facilitatingthe prevention of accidental needle sticks during use and otherwisefacilitating handling of the vial during filling and other processing.Another advantage of certain preferred embodiments of the presentinvention is that the stopper and vial may be assembled without humanintervention and prior to filling to thereby form hermetically sealed,empty vials that may be sterilized and maintained in the sterilizedcondition prior to filling. Yet another advantage of certain preferredembodiments of the present invention is that the plastic or liketamper-resistant portion allows the empty vials to be sterilized, suchas by the application of gamma, e-beam or other radiation thereto.

Other advantages of the present invention, and/or the disclosedembodiments thereof, will become more readily apparent in view of thefollowing detailed description of currently preferred embodiments andaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

So that those having ordinary skill in the art to which the presentapplication appertains will more readily understand how to make and usethe same, reference may be had to the drawings wherein:

FIG. 1 is a cross-sectional view of a prior art cap for a medicamentvial;

FIG. 2 is a cross-sectional view of a resealable stopper that may beemployed in any of the vial assemblies of the present disclosure;

FIG. 3 is a cross-sectional view of the resealable stopper of FIG. 2shown with an injection needle or syringe inserted through the stopperfor introducing medicament into the vial, and a venting needle orsyringe inserted through the stopper for venting the vial during fillingof the medicament;

FIG. 4 is a cross-sectional view of another embodiment of the resealablestopper and vial;

FIG. 5 is a cross-sectional view of the crimpable locking member of FIG.4 for securing the resealable cap to the vial;

FIG. 6 is a cross-sectional view of the base portion of the resealablestopper of FIG. 4 made of a material compatible with the predeterminedmedicament to be sealed within the vial, such as vulcanized rubber;

FIG. 7 is a cross-sectional view of the resealable portion of thestopper of FIG. 4 formed of a material that is fusible in response tothe application of thermal energy thereto in order to hermeticallyre-seal the stopper after inserting and removing a filling needle orlike instrument therethrough;

FIG. 8 is an enlarged, partial, cross-sectional view of the resealableportion of FIG. 7 and showing the penetrable portion thereof forreceiving a needle or like instrument therethrough;

FIGS. 9A through 9C are somewhat schematic, cross-sectional, sequentialviews illustrating an exemplary apparatus and method for sterilizing theresealable stoppers of the vials of the present disclosure by directheat cauterization prior to introducing the filling needle or likeinstrument therethrough;

FIG. 10 is a somewhat schematic, partial, cross-sectional view of anapparatus for sterilizing the resealable stoppers of the vials of thepresent disclosure by laser cauterization prior to introducing thefilling needle or like instrument therethrough;

FIG. 11 is a somewhat schematic, partial, cross-sectional view of anapparatus for needle filling the vial assemblies of the presentdisclosure with a predetermined medicament or other substance to becontained therein;

FIGS. 12a through 12d are somewhat schematic, cross-sectional,sequential views illustrating an apparatus and method for hermeticallysealing the penetrated region of the resealable stoppers of the vials ofthe present disclosure by direct heat sealing after withdrawing thefilling needle therefrom;

FIGS. 13A through 13C are somewhat schematic, cross-sectional,sequential views illustrating an apparatus and method for hermeticallysealing the penetrated region of the resealable stoppers of the vials ofthe present disclosure by laser sealing after withdrawing the fillingneedle therefrom;

FIG. 14A is a side elevation view of a vial embodying the presentdisclosure;

FIG. 14B is a cross-sectional view of the vial of FIG. 14A taken alongline 14B-14B and illustrating a three-piece closure assembly partiallyinserted into the mouth of the vial, wherein the closure assemblyincludes a stopper, a heat-resealable portion and an over-moldedsecuring or locking ring;

FIG. 14C is a cross-sectional view of the over-molded vial of FIG. 14taken along line 14C-14C thereof, wherein the vial has a relativelyenlarged base portion;

FIG. 15 is a cross-sectional view of another vial embodying the presentdisclosure, and including a closure or cap wherein the over-moldedsecuring ring is formed in an annular recess defined between the outerperiphery of the stopper and the vial body;

FIGS. 16A and 16B illustrate representative sequential views of anexemplary over-molding process for making over-molded vials embodyingthe present disclosure;

FIGS. 17A through 17C are cross-sectional, sequential views of analternate over-molding process for making over-molded vials embodyingthe present disclosure, wherein both the vial closure and the baseportion of the vial are formed by injection molding;

FIG. 18 is a cross-sectional view of another vial embodying the presentdisclosure wherein the base and locking ring are snap fit to the vialbody, and the tamper-resistant cover is snap fit to the locking ring;

FIG. 19 is a cross-sectional view of another vial embodying the presentdisclosure wherein the stopper and securing ring are formed using asequential molding process;

FIG. 20 is a cross-sectional view of the stopper of the vial of FIG. 19;

FIG. 21 is a cross-sectional view of the stopper and securing ring ofthe vial of FIG. 19;

FIG. 22A is a perspective view of the vial of FIG. 18 with thetamper-resistant cover removed;

FIG. 22B is a perspective view of the vial of FIG. 18 including thetamper-resistant cover fixedly secured thereto;

FIG. 22C is a perspective view of the vial of FIG. 18 illustrating thefrangible portion of the tamper-resistant cover flipped upwardly toexpose the resealable stopper and allow same to be penetrated with theneedle of a syringe to withdraw the medicament of other substancecontained within the vial into the syringe;

FIG. 23 is a side elevation view of another vial embodying the presentdisclosure wherein the locking ring, cover and base are connectedtogether by ultrasonic welding;

FIG. 24 is a cross-sectional view of the vial of FIG. 23;

FIG. 25 is a partially exploded, perspective view of the vial of FIG.23;

FIG. 26 is a perspective view of the vial assembly of FIG. 23 with thetamper-resistant cover removed;

FIG. 27 is an exploded, perspective view of the vial of FIG. 23;

FIG. 28 is partially cut-away, perspective view of the vial of FIG. 23;

FIG. 29 is a cross-sectional view of another vial embodying the presentdisclosure;

FIG. 30 is a perspective, exploded view of the vial of FIG. 30;

FIG. 31 is a perspective, partial, cut-away view of the vial of FIG. 30;

FIG. 32 is a perspective, partly exploded view of a needle manifold usedin a needle filling module of a sterile filling machine for needlefilling the vials with a medicament or other substance to be containedtherein;

FIG. 33 is a front perspective view of the needle manifold of FIG. 32located in an “up” position within a sterile enclosure of a sterilefilling machine, and with a plurality of vials mounted within atransport system including a star wheel and associated guide, that arealigned with the needles and ready for needle filling;

FIG. 34 is a front perspective view of the needle manifold and transportsystem of FIG. 33 showing the needle manifold in a “down” position withthe needles penetrating the resealable stoppers of the vials and fillingthe interiors of the vials with a medicament or other substance to becontained therein;

FIG. 35 is a rear perspective view of the needle manifold and transportsystem of FIG. 33 showing the needle in the “down” or fill position;

FIG. 36 is a perspective view of a laser sealing and infrared sensemanifold mounted downstream of the needle manifold of FIGS. 32-35 in asterile enclosure of a sterile filling machine for laser resealing theneedle holes in the filled vials;

FIG. 37 is a partly exploded, end elevation view of a module including aneedle manifold, laser optic assemblies, and sensors, for needle fillingand laser resealing the vials therein, and with some parts removed forclarity;

FIG. 38 is an end elevation view of the module of FIG. 37 showing theneedle manifold clamped to the drive plate, and with some parts removedfor clarity;

FIG. 39A is an end elevation view of the module of FIG. 37, with partsremoved for clarity, without any vials received within the module, andshowing the needles in the “up” position;

FIG. 39B is an end elevation view of the module of FIG. 39A showingvials received within the module and ready to be needle pierced andfilled;

FIG. 39C is an end elevational view of the module of FIG. 39A showingthe needle manifold in the “down” position with the needles piercing theresealable stoppers for allowing the medicament or other substance to bepumped through the needles to fill the vials;

FIG. 40A is an end elevation view of the module with parts removed forclarity, and showing an exemplary laser optic assembly and sensor;

FIG. 40B is an end elevation view of the module of FIG. 40A showing theneedle piercing the resealable stopper to, in turn, fill the interiorchamber of the respective vial with a medicament or other substance tobe contained therein;

FIG. 40C is an end elevation view of the module of FIG. 40A showing theneedle removed from the resealable stopper, the laser beam beingtransmitted onto the penetration point of the needle, and the IR sensorsensing the temperature of the resealed portion of the stopper to ensurethe integrity of the seal;

FIG. 41 is a partly exploded view of the needle manifold of the modulewith some parts removed for clarity;

FIG. 42 is a perspective view of the module showing an e-beam unitmounted within the module for sterilizing selected surfaces of the vialand needles located within the module chamber, and with the needlemanifold and other parts removed for clarity;

FIG. 43 is a top plan, somewhat schematic view of the module mountedadjacent to a screw-type conveyor for driving the vials through themodule;

FIG. 44 is a top plan, somewhat schematic view of the module mountedadjacent to a closed-loop conveyor, an inlet conveyor for transferringthe empty vials onto the closed loop conveyor, and an outlet conveyorfor receiving the filled and resealed vials;

FIG. 45 is a cross-sectional view of another vial embodying the presentdisclosure wherein the filling needle may penetrate the stopper in amarginal portion of the penetrable region of the stopper at an acuteangle relative to the axis of the vial, and the resealed portion of thestopper may be concealed under the tamper-resistant cover upon removingthe frangible portion thereof;

FIG. 46 is an upper perspective view of the vial of FIG. 45 with thetamper-resistant cover removed;

FIG. 47 is another cross-sectional view of the vial of FIG. 45 includingthe tamper-resistant cover secured thereto, and illustrating the mannerin which the laser resealed portion of the stopper is visually concealedunder the tamper-resistant cover upon removal of the frangible portionthereof; and

FIG. 48 is an upper perspective view of the vial of FIG. 47.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

Reference is now made to the accompanying figures for the purpose ofdescribing, in detail, preferred embodiments of the present disclosure.The figures and accompanying detailed description are provided asexamples of the disclosed subject matter and are not intended to limitthe scope thereof.

Turning to FIG. 2, a heat-resealable cap or stopper that may be used inthe vials of the present invention is indicated generally by thereference numeral 110. The cap 110 includes a resilient base 112 made ofvulcanized rubber or like material which is known to those of ordinaryskill in the pertinent art, and acceptable for use in the manufacture ofend caps or the portions thereof placed in contact with, or otherwiseexposed to medicaments or other substances to be contained in the vials,such as vaccines. The base 112 defines a lower peripheral wall 115shaped and dimensioned to be slidably received within the open end of avial 114. The vial 114 may be made of any of numerous different types ofglass or plastic, or any other material that is currently or laterbecomes known for use in connection with making vials, such as vials forstoring medicaments or other substances. The vial 114 defines therein achamber 116 for receiving medicament. As described further below, thevial preferably defines a “diabolo” or spool-like shape to, for example,facilitate handling of the vial during sterilization, filling and/orother processing of the vial, and during use of the vial. The base 112of the cap 110 further defines an upper peripheral wall 117 also shapedand dimensioned to be slidably received within the open end of the vial114, and a peripheral sealing flange 118 projecting outwardly from theupper end of the peripheral wall 117. The vial 114 defines at its openend a peripheral flange 120. As shown in FIGS. 2 and 3, the peripheralflange 118 of the base 112 sealingly engages the peripheral flange 120of the vial 114 to seal the interface between the cap and vial. The base112 further defines an upper recess 122 formed within the upperperipheral wall 117, and an annular rim 124 projecting inwardly from theupper end of the peripheral wall.

A resealable portion 126 is fixedly received within the upper recess 122of the base 112 to form the assembled cap 110. The resealable portion126 defines an upper peripheral flange 128, an annular recessed portionor recess 130, and a base 132 located on the opposite side of theannular recess 130 relative to the flange, and projecting outwardly fromthe recess. As can be seen in FIGS. 2 and 3, the annular recess 130 andbase 132 of the resealable portion 126 are dimensioned and shapedcomplementary to (or define the mirror image of) the interior surfacesof the upper recess 122 and annular rim 124 of the base 112.Accordingly, the resealable portion 126 is pressed, snapped or otherwisereceived within the upper recess 122 such that the annular rim 124 isreceived within the annular recess 130 to thereby fixedly secure theresealable portion within the base.

The resealable portion 126 is preferably made of a resilient polymericmaterial, such as a blend of a first polymeric material sold under theregistered trademark KRATON® or DYNAFLEX® and a second material in theform of a low-density polyethylene, such as the polyethylene sold by DowChemical Co. under the trademarks ENGAGE™ or EXACT™. In someembodiments, the first and second materials are blended within a rangeof about 50:50 by weight to about 90:10 by weight (i.e., firstmaterial:second material). In one embodiment, the blend of the first andsecond materials is about 50:50 by weight. The benefits of the preferredblend over the first material by itself are improved water or vaporbarrier properties, and thus improved product shelf life; improved heatsealability; a reduced coefficient of friction; improved moldability ormold flow rates; and a reduction in hysteresis losses. As may berecognized by those skilled in the pertinent art, these numbers andmaterials are only exemplary, however, and may be changed if desired orotherwise required.

An important feature of the resealable portion 126 is that it beresealable to form a gas-tight seal after inserting a needle, syringe orlike injection member through the resealable member. Preferably, theresealable portion can be sealed by heating the area punctured by theneedle as described further below. One advantage of the blended polymerdescribed above is that it is known to minimize the degree to which themedicament can be absorbed into the polymer in comparison to eitherKRATON® or DYNAFLEX® itself.

An aluminum locking or crimping ring 134 defining an upper peripheralflange 136 and a lower peripheral flange 138 may be mounted over the endcap 110 and vial 114. The upper and lower flanges 136 and 138,respectively, of the locking ring are crimped or otherwise pressedagainst the adjacent surfaces of the cap and vial to press the sealingflanges of the cap against the vial and thereby maintain a fluid-tightand/or gas-tight seal between the cap and vial. Alternatively, thelocking ring may be formed of a non-metallic material, such as a plasticmaterial, that may be snap-fit to the underside of the peripheral flange120, or otherwise secured to the flange of the vial body, as describedfurther below.

As shown in FIG. 3, the heat-resealable cap 110 is shown with ahypodermic or other type of needle 140 inserted through the resealableportion 126 and the resilient base 112 in order to dispense medicamentinto the chamber 116 of the vial. A venting needle 142 likewise may beinserted through the resealable portion 126 and the resilient base 112in order to allow gas to escape from the vial 114 as the medicament isdeposited into the vial. Alternatively, the needle 140 may define one ormore axially-elongated grooves in an outer surface thereof to allow gaswithin the vial to vent therethrough and thereby eliminate the need forthe venting needle 142, or the needle may take the form of a “double” or“multi” lumen needle wherein the one lumen of the needle delivers themedicament or other substance to be contained within the vial, andanother lumen permits the gas displaced by the medicament or othersubstance to flow out of the vial. The apparatus and method fordispensing medicament or other substances into the vial may take a formas shown in U.S. Pat. No. 5,641,004 to Daniel Py, issued Jun. 24, 1997,and more preferably, may take a form as shown in U.S. Provisional PatentApplication No. 60/484,204, filed Jun. 30, 2003, entitled “MedicamentVial Having A Heat-Sealable Cap, And Apparatus And Method For FillingThe Vial,” each of which is hereby expressly incorporated by referenceas part of the present disclosure.

In operation, the resealable portion 126 is inserted into the base 112,and the assembled end cap 110 is slidably inserted into the open end ofthe vial 114. The locking ring 134 is then crimped in place to lock thecap 110 to the vial and maintain the gas-tight seal at the interface ofthe cap and vial. The assembled cap 110 and vial 114 preferably are thensterilized, such as by exposing the assembly to irradiation, such aslaser, beta, gamma or e-beam radiation, in a manner known to those ofordinary skill in the pertinent art. The medicament-dispensing needle140 is then inserted through the resealable portion 126 and theresilient base 112 until the free end of the needle is received into thechamber 116 of the vial to, in turn, dispense medicament into thechamber. The venting needle 142 is likewise inserted through theresealable portion 126 and the resilient base 112 in order to draw gasfrom the sealed vial as the liquid medicament is deposited within thechamber of the vial. Once the medicament has been deposited within thechamber of the vial, the needles 140 and 142 are withdrawn from the cap110, and as described further below, a heat or other energy source isapplied to the portions of the resealable portion 126 punctured by theneedles 140 and 142 to, in turn, seal the punctured areas andhermetically seal the medicament within the vial.

One advantage of the illustrated vial assemblies is that the stopper maybe resealed following the deposit of medicament into the interior of thevials, thereby rendering the vials particularly suitable for use withpreservative-free medicaments, such as preservative-free vaccines.Accordingly, a further advantage of the illustrated vial assemblies isthat the medicament need not contain a preservative, and therefore theabove-described drawbacks and disadvantages of such preservatives can beavoided.

Another advantage of the illustrated vial assemblies is that themedicament within the resealed chambers of the vials is not contaminatedor otherwise affected by impurities or other agents in the atmospherewhere the vial is stored or transported.

In FIGS. 4 through 8 another resealable stopper or cap that may beemployed in the vials of the present invention is indicated generally bythe reference numeral 210. The resealable stopper 210 is essentially thesame as the stopper 110 described above, and therefore like referencenumerals preceded by the numeral “2” instead of the numeral “1” are usedto indicate like elements. As shown best in FIGS. 4 and 6, the base 212of the cap defines on the interior side of its upper peripheral wall 217an annular groove 230. As shown best in FIGS. 4 and 7, the resealableportion 226 defines on the peripheral surface of its base 232 an annularraised portion or protuberance 224 dimensioned to be frictionallyreceived within the corresponding annular groove 230 of the base 212 tothereby secure the resealable portion to the base. As shown in FIG. 6,the base 212 further defines on the exterior side of its lowerperipheral wall 215 a plurality of raised annular portions orprotuberances 244 axially spaced relative to each other for frictionallyengaging the interior wall of the vial 214 to thereby secure the capwithin the vial and facilitate maintaining a hermetic seal between thecap and vial. As shown best in FIGS. 7 and 8, the resealable portion 226defines on its top surface an annular raised portion or protuberance 246defining a circular surface portion 248 therein for receiving a fillingneedle or like instrument, as described further below. As shown in FIG.5, the locking or crimping ring 234 defines a central aperture 250 inits upper side for receiving therethrough the annular raised portion 246of the resealable portion 226.

Preferably, the resealable cap 210 and vial 214 are assembled and thelocking ring 234 is crimped or otherwise secured in place as describedabove and shown in FIG. 4 prior to introducing any medicament or otherfluid into the vial. Then, one or more of the empty cap/vial assembliesare enclosed, sterilized, and may be transported in accordance with theteachings of the present inventor's commonly owned U.S. Pat. No.5,186,772, entitled “Method Of Transferring Articles, Transfer PocketAnd Enclosure,” and/or U.S. patent application Ser. No. 10/241,249,entitled “Transfer Port And Method For Transferring Sterile Items,”filed Sep. 10, 2002, each of which is hereby expressly incorporated byreference as part of the present disclosure. The empty cap/vialassemblies may be placed in an internal bag or “pocket” which is closedand, if desired, provided with a sterilization indicator. Then, theinternal pocket may be placed within a transfer pocket including asealing frame defining an annular groove on a peripheral surfacethereof. The transfer pocket is stretched over the surface of the frameand closed by an elastic band overlying the transfer pocket and receivedwithin the peripheral groove. The transfer pocket likewise may includetherein a sterilization indicator. Preferably, the assembled transferand internal pockets are sealed within an “external” pocket and theassembled pockets are subject to sterilization, such as by exposure togamma radiation, to sterilize the pockets and the empty cap/vialassemblies within the pockets. The transfer pockets then can be used tostore and/or transport the sterilized assemblies to a filling systemwithout contaminating the sterilized assemblies. As further described inthe above-mentioned patent and patent application, the filling system islocated within a sterile enclosure, and the empty vials are introducedinto the enclosure by removing and discarding the external pocket, andconnecting the sealing frame of the transfer pocket to a window ortransfer port of the enclosure. As further disclosed in theabove-mentioned patent and patent application, an adhesive material ispreferably superimposed on the sealing frame for securing the transferpocket to the transfer port of the filling system enclosure. Prior toreleasing the vial assemblies into the filling system enclosure, thesterilization indicators may be checked in order to ensure that thesterile condition of the vial assemblies were maintained throughoutstorage and transfer. As described in the above-mentioned patent andpatent application, the portion of the transfer pocket overlying theframe is then cut away and simultaneously sterilized along the trimmedsurfaces to destroy any microorganisms or germs thereon, and to allowthe internal pocket to be received through the transfer port and intothe enclosure.

Once received within the enclosure, the internal pocket is opened andthe empty vial assemblies are removed and loaded into a filling machinelocated within the sterile enclosure. Once loaded into the fillingmachine, the resealable portion of each empty vial assembly may besterilized again in order to further ensure that no contaminates enterthe vial during the filling process. The resealable portions of thestoppers may be sterilized at this stage by direct heat cauterization,laser cauterization, or the application of another form of radiation,such as e-beam radiation.

As shown in FIGS. 9A through 9C, an apparatus for cauterizing theresealable stoppers or caps by application of heat thereto is indicatedgenerally by the reference numeral 252. The apparatus 252 comprises ahousing 254 mounted over a vial support 256. The vial support 256 may beadapted to hold a single vial, or preferably, is adapted hold aplurality of vials. The embodiment of the support adapted to hold aplurality of vials defines a channel 258 for receiving therein thevials, and a pair of opposing shoulders 260 formed at the upper edge ofthe channel for supporting thereon the flange 220 of the vial. Ifdesired, a vibratory drive (not shown) may be drivingly connected to thesupport 256 to vibrate the support and, in turn, move the vials throughthe channel at a predetermined rate. Alternatively, the vial support 256may be mounted on, or otherwise take the form of a conveyor for movingthe vials through the sterile filling machine. As may be recognized bythose skilled in the pertinent art based on the teachings herein,however, any of numerous different drive systems that are currently, orlater become known, may be equally employed to move the vials throughthe filling machine.

The housing 254 defines a peripheral sealing surface 262 formed on thefree end of the housing for sealingly engaging the upper flange surface236 of each locking member 234. As shown best in FIG. 9b , theperipheral sealing surface surrounds the aperture 250 formed through thelocking member and exposing the penetrable region 248 of the resealableportion 226 of the stopper. Preferably, the peripheral sealing surface262 forms a substantially fluid-tight seal between the housing and thestopper. A heating surface 264 projects outwardly from the free end of acentral support 266 of the housing for contacting the penetrable surface248 of the resealable portion and cauterizing the surface. An annularconduit 268 extends about the periphery of the heating surface 264 andis coupled in fluid communication to a vacuum source 270 for drawing airthrough the conduit and away from the cauterized surface 248, asindicated by the arrows in the Figures. The housing 254 is drivinglyconnected to a drive source 272 for moving the housing and thus theheating surface 264 into and out of engagement with the exposedpenetrable surface portion 248 for cauterizing the surface, as indicatedby the arrows in the Figures. As may be recognized by those skilled inthe pertinent art based on the teachings herein, the drive source 272may take the form of any of numerous different types of drive sourcesthat are currently, or later become known, for performing the functionof the drive source as described herein, such as a pneumatic drive, or asolenoid-actuated or other type of electric drive. Similarly, theheating surface 264 may take any of numerous different shapes andconfigurations, and may be heated in any of numerous different ways thatare currently or later become known, such as by an electric resistanceheater (or “hot wire”). Preferably, however, the heating surface 264defines a surface shape and contour corresponding to the desired shapeand contour of the penetrable surface region 248 of the cap.

In the operation of the apparatus 252, and as shown typically in FIG.9A, each vial is first introduced into the cauterizing station with thepenetrable surface region 248 of the resealable portion 226 aligned withthe heating surface 264. Then, the drive source 272 is actuated to drivethe housing 254 downwardly until the peripheral sealing surfaces 262sealingly engage the upper flange surface 236 of the respective lockingmember 234, and the heating surface 264 simultaneously engages theexposed penetrable surface portion 248 of the resealable portion 226.The heated surface 264 is maintained at a predetermined temperature, andis held in contact with the exposed surface portion 248 for apredetermined time period, sufficient to cauterize the exposed surfaceportion. One advantage of the construction of the resealable portion 226as shown in FIGS. 7 and 8, is that the cauterization process deforms theannular protuberance 246 into a contour conforming to that of the heatedsurface, thus allowing an operator (or optical or other automaticsensing system) to visually determine whether each cap has been properlycauterized prior to filling. As shown in FIG. 9c , after cauterizing theexposed surface, the drive source 272 is actuated to drive the housing254 upwardly and out of engagement with the cap, another vial is movedunder the housing, and the process is repeated until all desired vialsare cauterized. As described further below, upon exiting the cauterizingstation of FIGS. 9A through 9 c, the vials are preferably then movedinto a filling station to promptly fill the sterilized vials. Thecauterization and filling stations are preferably mounted within asterile enclosure with a laminar gas flow through the enclosure tofacilitate maintaining the sterile conditions, as described, forexample, in the above-mentioned patent and patent application.

In the embodiment illustrated in FIGS. 9A through 9C, the temperature ofthe heating surface is within the range of approximately 250° C. to 300°C., and the cycle times (i.e., the time period during which the heatingsurface is maintained in contact with the exposed surface 248 of theresealable portion) are within the range of approximately 1.0 to 3.0seconds. The present inventor has determined that these temperatures andcycle times may achieve at least approximately a 6 log reduction inbio-burden testing to thereby effectively sterilize the surface.

In FIG. 10, an alternative apparatus for cauterizing the resealable capsis indicated generally by the reference numeral 274. The apparatus 274differs from the apparatus 252 of FIGS. 9A through 9C in that thethermal energy required for sterilizing the filling area of theresealable portion is supplied by a laser (referred to herein as “lasercauterization”). The laser cauterization apparatus 274 comprises a laseror other suitable radiation source 276 optically coupled to a scanningmirror 278 mounted over the vial/cap assembly. Although not shown inFIG. 10, the vials are preferably mounted within the same type ofsupport as shown in FIGS. 9A through 9C in order to allow the resealablecaps to be rapidly cauterized in succession prior to filling each vialwith medicament, as described further below.

In one embodiment, the laser 276 is a commercially available CO2 or YAGlaser. The CO2 laser operates at a wavelength of approximately 10.6 μm.At this wavelength, absorption of the laser energy is governed in partby the electrical conductivity of the material. Therefore, an insulatingmaterial, such as the elastomeric material of the resealable portion226, absorbs and converts most of the incident energy into thermalenergy to cauterize the receiving surface 248. The YAG laser operates atwavelength of approximately 1.06 μm. At this frequency, absorption isgoverned in part by the lattice atoms. Thus, a clear or transparentpolymer with little ionization would be permeable to the laser beam.Accordingly, when employing a YAG laser (as with other laser sources, asdescribed below), it is desirable to add a colorant to the elastomericmaterial of the resealable portion in order to enhance its absorption ofthe laser energy. With the YAG laser, the superficial layer of thepenetrable region of the resealable portion, and any germs, bacteria orother contaminants thereon, are transformed into plasma to rapidly andthoroughly sterilize the effected surface. If necessary, a UV-filtrationcoating may be applied to the surfaces of the sterile filling enclosureto prevent the operators from receiving any unnecessary UV exposure.

The present inventor has demonstrated that beam energies in the range ofapproximately 15 to 30 W are sufficient to effectively cauterize thesurface 248 of the elastomeric resealable portion. In addition,bio-burden testing has demonstrated that laser energies of approximately20 W or greater may achieve about a 6.0 log reduction. At theseenergies, the apparatus may effectively sterilize the surface 248 withina cycle time of approximately 0.5 seconds. Accordingly, a significantadvantage of the laser cauterization apparatus and method is that theymay involve significantly shorter cycle times than various direct heatmethods. Yet another advantage of laser cauterization, is that itinvolves both a non-contact method and apparatus, and therefore there isno need to be concerned with the cleaning of a contact head or likeheating surface.

Turning to FIG. 11, after direct heat or laser cauterization of theresealable portion 226 of each vial, the vial is moved within thesupport 256 (such as by vibratory drive) into a filling station 280. Thefilling station 280 includes a needle or like injection member 282reciprocally mounted over the support 256, as indicated by the arrows inFIG. 11, and axially aligned with the penetrable region 248 of theresealable portion 226 of each vial assembly passing therethrough. Adrive source 284 is drivingly connected to the needle 280 forreciprocally driving the needle 282 into and out of engagement with eachcap or stopper 210. A medicament or other formulation reservoir 286 iscoupled in fluid communication with the needle 282 for introducing apredetermined medicament or other formulation through the needle andinto the vial. In the illustrated embodiment, the needle 282 defines aplurality of fluid conduits therein, including a first fluid conduit 288for injecting the predetermined medicament or other formulation into thevial, as indicated by the arrow in FIG. 11, and a second fluid conduit290 coupled in fluid communication with a vacuum source 292 forwithdrawing air or other gases from the interior cavity 216 of the vialprior to and/or during the filling of the cavity with the medicament orother formulation. In the illustrated embodiment, the needle 282 is a“double lumen” needle, defining a central fluid conduit 288 forinjecting the predetermined medicament or other formulation into thevial, and an outer annular fluid conduit 290 for drawing the displacedair or other gases out of the interior cavity of the vial.Alternatively, the outer fluid conduit 290 of the double-lumen needlemay be defined by one or more axially-elongated grooves formed in theouter wall of the needle that form fluid-flow passageways between theneedle and the pierced portion of the resealable stopper. As may berecognized by those of ordinary skill in the pertinent art based on theteachings herein, the needles used to needle fill the vial assemblies ofthe present invention may take any of numerous different shapes and/orconfigurations that are currently known, or later become known forperforming the functions of the needles as described herein.

As shown in FIGS. 12a through 12d , after filling the vial with themedicament or other formulation and withdrawing the needle 282 from thecap or stopper 210, the penetrated region of the cap defines a needlehole 294 along the path of the withdrawn needle (FIG. 12b ). Uponwithdrawing the needle, the vulcanized rubber base 212 of the stopper issufficiently resilient to close upon itself in the penetrated region andthereby maintain the vial in a sealed condition. However, as describedabove, vapors, gases and/or liquid may be allowed over time to passthrough the needle hole of the vulcanized rubber base, and thereforeeach vial/cap assembly is passed through a sealing station, as showntypically in FIG. 12c , to heat seal the resealable portion 226 of thecap promptly after withdrawing the needle therefrom. As shown typicallyin FIG. 12c , a heated member or surface 264 may be reciprocally mountedover, and axially aligned with the penetrable region 248 of the vial/capassembly received within the filling station. A drive source 272 isdrivingly connected to the heated member 264 to reciprocally drive theheated member into and out of engagement with the resealable portion ofeach cap. As shown typically in FIG. 12c , the heated member 264 ismaintained at a sufficient temperature, and maintained in engagementwith the penetrated region of the resealable portion 226 to fuse theelastomeric material and hermetically seal the needle hole 294. As aresult, and as shown typically in FIG. 12d , the needle hole iseliminated from the exterior region of the resealable portion to therebymaintain a hermetic seal between the cap and vial.

As may be recognized by those skilled in the pertinent art based on theteachings herein, the drive source and heating member/surface of FIGS.12a through 12d may take the form of any of numerous different drivesources and heating members as described above. As indicated typicallyin FIG. 12c , however, the heating member 264 may define a smaller widththan the heating member/surface described above for cauterizing thepenetrable region of the cap prior to filling. In addition, thetemperature of the heating member 264 for sealing may be higher thanthat of the heating member described above in order to rapidly melt andseal the penetrated region. One advantage of resealable stoppers is thatthe base thermally insulates the heated region from the medicament inthe vial to thereby maintain the medicament in the vial within anappropriate temperature range throughout the cauterization and heatsealing processes and thereby avoid any thermal damage to themedicament.

Alternatively, and as shown in FIGS. 13A through 13C, the laser source276 and scanning mirror 278 may be employed to heat seal the penetratedregion 294/248 of the resealable portion. Accordingly, the same type oflaser source 276 and scanning mirror 278 as described above may beemployed in the heat sealing station to perform this function, oralternatively, a different type of laser system may be employed. In oneembodiment, a CO2 laser of approximately 50 W is employed to seal aregion approximately 0.10 inch in diameter in the resealable stopper.

In some embodiments of the present disclosure, each sealable cap orstopper is formed of a thermoplastic material defining a needlepenetration region that is pierceable with a needle to form a needleaperture therethrough, and is heat resealable to hermetically seal theneedle aperture by applying laser radiation at a predeterminedwavelength and power thereto. As described further below, each cap orstopper includes a thermoplastic body or body portion defining (i) apredetermined wall thickness in an axial direction thereof, (ii) apredetermined color and opacity that substantially absorbs the laserradiation at the predetermined wavelength and substantially prevents thepassage of the radiation through the predetermined wall thicknessthereof, and (iii) a predetermined color and opacity that causes thelaser radiation at the predetermined wavelength and power tohermetically seal the needle aperture formed in the needle penetrationregion thereof in a predetermined time period and substantially withoutburning the needle penetration region and/or the cover portion of thestopper (i.e., without creating an irreversible change in molecularstructure or chemical properties of the material). In some embodiments,the predetermined time period is approximately 2 seconds, and ispreferably less than or equal to about 1.5 seconds. In some of theseembodiments, the predetermined wavelength of the laser radiation isabout 980 nm, and the predetermined power of each laser is preferablyless than about 30 Watts, and preferably less than or equal to about 10Watts, or within the range of about 8 to about 10 Watts. Also in some ofthese embodiments, the predetermined color of the material is gray, andthe predetermined opacity is defined by a dark gray colorant added tothe stopper material in an amount within the range of about 0.3% toabout 0.6% by weight.

In addition to the thermoplastic materials described above, thethermoplastic material may be a blend of a first material that ispreferably a styrene block copolymer, such as the materials sold undereither the trademarks KRATON or DYNAFLEX, such as DYNAFLEXG2706-10000-00, and a second material that is preferably an olefin, suchas the materials sold under either the trademarks ENGAGE or EXACT, suchas EXACT 8203. In some embodiments of the invention, the first andsecond materials are blended within the range of about 50:50 by weightto preferably about 90:10 by weight, and most preferably about 90:5 byweight (i.e., first material:second material). The benefits of thepreferred blend over the first material by itself are improved water orvapor barrier properties, and thus improved product shelf life; improvedheat sealability; a reduced coefficient of friction; improvedmoldability or mold flow rates; and a reduction in hysteresis losses.

Alternatively, the thermoplastic material of the resealable stoppers maytake the form of a styrene block copolymer sold by GLS Corporation ofMcHenry, Ill. under the designation LC 254-071. This type of styreneblock copolymer compound exhibits approximately the following physicalproperties: (i) Shore A Hardness: about 28-29; (ii) Specific Gravity:about 0.89 g/cm3; (iii) Color: approximately grey to dark grey; (iv)300% Modulus, flow direction: about 181-211 psi; (v) Tensile Strength atBreak, flow direction: about 429-498 psi; (vi) Elongation at Break, flowdirection: about 675%-708%; and (vii) Tear Strength, flow direction:about 78-81 lbf/in. In one embodiment, the predetermined color andopacity of the thermoplastic is defined by a grey colorant that isprovided in an approximately 3% color concentrate (i.e., there is anapproximately 33:1 ratio of the concentrate to the natural resin orTPE). The color concentrate contains about 88.83% carrier or base resin,and the remainder is pigment. In one embodiment, the pigment is greycarbon black. Thus, the pigment is about 0.34% by weight of theresulting thermoplastic.

In addition, if desired, a lubricant of a type known to those ofordinary skill in the pertinent may be added to the thermoplasticcompound, such as the aforementioned styrene block copolymer compound,in order to prevent or otherwise reduce the formation of particles uponpenetrating the needle penetration region of the thermoplastic portionwith a needle or other filling member. In one embodiment, the lubricantis a mineral oil that is added to the styrene block copolymer or otherthermoplastic compound in an amount sufficient to prevent, orsubstantially prevent, the formation of particles upon penetrating samewith the needle or other filling member. In another embodiment, thelubricant is a silicone, such as the liquid silicone sold by Dow CorningCorporation under the designation “360 Medical Fluid, 350 CST,” that isadded to the styrene block copolymer or other thermoplastic compound inan amount sufficient to prevent, or substantially prevent, the formationof particles upon penetrating same with the needle or other fillingmember.

Each of the vials of the present invention may be made of any ofnumerous different materials that are currently, or later become knownfor making vials. For example, in some embodiments of the presentinvention, the vials are made of glass. In one such example, the vialbody is made of glass; however, a laterally extending base is made ofplastic, and is secured to the base of the glass vial body by anadhesive, snap-fit, over-molding, or other known joining mechanism, andthe locking ring likewise is made of plastic and is secured to the openend of the vial body by an adhesive, snap-fit, over-molding, or otherknown joining mechanism. In other currently-preferred embodiments of thepresent invention, the vial bodies are made of a thermoplastic material,such as the thermoplastic material sold under the trademark TOPAS byTicona Corp. of Summit, N.J. In some embodiments of the presentinvention, the TOPAS™ material is sold under any of the followingproduct codes: 5013, 5513, 6013, 6015, and 8007, and is a cyclic olefincopolymer and/or cyclic polyolefin.

As may be recognized by those skilled in the pertinent art based on theteachings herein, the specific formulations of the polymeric compoundsused to form the stoppers and the vials or other containers of thepresent invention can be changed as desired to achieve the desiredphysical characteristics, including sorption (both absorption andadsorption), and moisture-vapor transmission (“MVT”). For example, thewall thicknesses of the vials and/or stoppers can be increased orotherwise adjusted in order to provide an improved or otherwise adjustedMVT barrier. Alternatively, or in conjunction with such measures, theblend of components forming the thermoplastic compounds may be changedas desired to meet desired sorption levels with the particularproduct(s) to be contained within the vial, and/or to achieve desiredMVT characteristics. Still further, in those embodiments of theresealable stopper of the present invention employing multiple layers offusible and infusible materials, the relative thicknesses of thedifferent materials can be adjusted to, in turn, adjust the MVTcharacteristics of the stopper. In addition, as described further below,a tamper-resistant or other cover, that may include a frangible or likeportion that is removable immediately prior to use of the vial to exposethe resealable stopper, can form a hermetic or gas-tight seal betweenthe needle penetrable surface of the stopper and the ambient atmosphere,to further improve the MVT barrier to medicament or other substancecontained within the vial. As also may be recognized by those ofordinary skill in the pertinent art based on the teachings herein, theabove-mentioned numbers and materials are only exemplary, and may bechanged as desired or otherwise required in a particular system.

Referring now to FIGS. 14A through 14C, a further embodiment of anassembled medicament vial constructed in accordance with the inventiveaspects of the present disclosure is

designated generally by reference numeral 300. Vial assembly 300includes, among other things, a storage vial 310, a stopper member 330,a securing ring 350 and a heat resealable disc 370.

Storage vial 310 includes a body 312, a base 314 and a neck 316. Body312 defines an interior chamber 318 that is adapted for storing apredetermined medicament or other substance to be contained therein. Asshown herein, body 312 is substantially cylindrical in shape. However,those skilled in the art would readily appreciate that body 312 can bespherical or any other shape conducive to defining an interior chambersuitable for the storage of medicaments or other substances. Neck 316 isassociated with the top of body 312 and defines a vial mouth 320. In thecurrently preferred embodiments, medicament flow into and out of theinterior chamber 318 is through a needle (both directions).

Stopper member 330 is inserted into mouth 320 and includes an outerperipheral surface 332 which is adapted and configured for insertioninto mouth 320 and for engagement with neck 316 of storage vial 310. Thestopper member 330 provides a first primary seal for containing thepredetermined medicament within the interior chamber 318 of storage vial310. Stopper member 330 may be formed of vulcanized rubber. However,those skilled in the art to which this application appertains wouldreadily appreciate that other suitable materials may be used for stoppermember 330.

Heat-resealable portion 370 is also inserted into the mouth 320 ofstorage vial 310 and preferably completely overlies stopper member 330.As described above with respect to the other embodiments of theresealable stopper, heat-resealable portion 370 is preferably made of aresilient polymeric material, such as a blend of a first polymericmaterial sold by Shell Oil Co. under the registered trademark KRATON® orDYNAFLEX®, and a second material in the form of a low-densitypolyethylene, such as the polyethylene sold by Dow Chemical Co. underthe trademarks ENGAGE™ or EXACT™. In one embodiment, the first andsecond materials are blended within a range of about 50:50 by weight toabout 90:10 by weight (i.e., first material:second material). In anotherembodiment, the blend of the first and second materials is about 50:50by weight. The benefits of the preferred blend over the first materialby itself are improved water or vapor barrier properties, and thusimproved product shelf life; improved heat sealability; a reducedcoefficient of friction; improved moldability or mold flow rates; and areduction in hysteresis losses. As may be recognized by those skilled inthe pertinent art, these numbers and materials are only exemplary,however, and may be changed if desired or otherwise required in aparticular system.

An important feature of the heat-resealable portion 370 is that it canbe resealed to form a gas-tight seal after inserting a needle, syringeor like injection member therethrough. Preferably, the resealableportion can be sealed by heating the area punctured by the needle in themanner described above. One advantage of the blended polymer describedabove is that it minimizes the degree to which the medicament can beabsorbed into the polymer in comparison to either KRATON® or DYNAFLEX®itself.

With continuing reference to FIGS. 14A through 14C, securing ring 350 isshown engaged with the neck 316 of the vial 300 and is adapted andconfigured for retaining the heat-resealable portion 370 and the stoppermember 330 within the vial mouth 320 and effectuating a second seal. Thesecuring ring 350 is formed preferably from at least one of athermoplastic and elastic material. The securing ring can be formed froma resilient polymeric material and a low-density polyethylene, similarto that used in the heat-resealable portion 370. Preferably, thesecuring ring 350 is formed by inserting the storage vial 310/stoppermember 330 assembly into a molding apparatus and then molding thesecuring ring material directly over a portion of the storage vial 310and stopper member 330 (referred to as “over-molding”).

As noted above, it is difficult to maintain the sterility of caps andvials during the transportation, storage and assembly process. The useof a non-metallic material for securing ring 350 allows the vial and capto be assembled and then sterilized as a unit prior to filling the vialassembly with medicament by using, for example, a gamma sterilizationtechnique or other irradiation or sterilization process. Unlike threadedplastic caps, an over-molded securing ring provides a mechanism forensuring that the vial has not been compromised and prevents the stopperfrom being removed.

As shown in FIG. 14b , securing ring 350 defines a somewhat C-shapedcross-section having a web 356 that separates a lower flange 352 and anupper flange 354. The securing ring 350 is formed so that lower flange352 is engaged with shoulder 322 of storage vial 310. Additionally,upper flange 354 partially overlies stopper member 330 andheat-resealable portion 370 and thereby secures these elements withinthe mouth 320 of vial body 310.

During the over-molding process, if desired, the material used to formthe securing ring 370 can be provided to the mold at a temperature thatis sufficient to partially melt in the region of interface of the neck316 of the vial and/or the heat-resealable disc 370 or stopper member330. As a result, upon the cooling of the materials, the securing ring370 is effectively fused with the neck 316 of the vial and/or theheat-resealable portion 370 or stopper member 330. The fusing of thematerials further enhances the sealing and retaining function ofsecuring ring 350. Partial fusion of one or more of the elements asdescribed also is advantageous in vials having a relatively largediameter mouth, since the insertion of a needle into a stopper tends topush the stopper into the interior chamber. If necessary, the fusing ofthe securing ring with the stopper or heat-resealable portion mayfacilitate preventing the collapse of the stopper. It should be notedthat the fusion of the materials can be accomplished by ultrasonicwelding, by applying thermal energy or by using any other knowntechnique for joining thermoplastics, elastics or other materialsemployed.

It is presently envisioned that in an alternate embodiment, theheat-resealable disc can be removed and the securing ring can be formedso that it completely overlies the stopper member. In this embodiment,the securing ring could be formed of heat-resealable material that isthe same as or similar to that described for disc 370 or otherwisedescribed above. In operation, the stopper member and the securing ringwould be penetrable by a needle or like filling member for theintroduction of medicament into the interior chamber of the vial. Uponwithdrawal of the filling needle, thermal energy would be applied to thesecuring ring for hermetically sealing any hole created by the fillingneedle.

With continuing reference to FIGS. 14A through 14C, vial assembly 300further includes a peel back cover 380. Cover 380 is adhered to sealingring 350 subsequent to the filling and resealing processes and providesa tamper-proof seal which signifies whether medicament has beenwithdrawn or the vial tampered with subsequent to the filling processand vial storage. In addition, if necessary or otherwise desired, thepeel back cover can provide a further barrier to moisture and/or vaportransmission into or out of the interior of the vial.

As shown in FIG. 14A, the vial 310 defines a spool-like or diaboloshape. More specifically, the upper portion or securing ring 350 definesa first laterally-extending dimension or diameter “D1,” the vial body312 defines a second laterally-extending dimension or diameter “D2,” andthe base 314 defines a third laterally extending dimension or diameter“D3”. As can be seen, both D1 and D3 are greater than D2, thus forming adiabolo or spool-like shape. As described above, this shape facilitateshandling during use by permitting the user to grasp the reduced diameterD2 of the vial body with, for example, an index finger and thumb of onehand. The relatively larger diameter D1 of the upper portion andrelatively larger diameter D3 of the base facilitate a user's ability tosecure the vial against axial movement. Further, the relatively largerdiameter D1 of the upper portion facilitates in preventing needle sticksby guarding a user's fingers in the event the needle slips or otherwisemisses the stopper. In addition, as described further below, the diaboloor spool-like shape can cause the vial to define a lower center ofgravity than other prior art vials, and thus better prevent tipping ofthe vial during handling in, for example, an automated filling machine.As also described further below, the diabolo or spool-like shapefacilitates in securing and otherwise handling the vial during automatedsterilization, needle filling and/or thermal resealing of the vial.

Referring now to FIG. 15, another vial assembly constructed inaccordance with a representative embodiment of the present disclosure isdesignated generally by reference numeral 400. Vial assembly 400includes, among other things, a storage vial 410, a stopper member 430,and a securing ring 450. Storage vial 410 has a cylindrical body 412which interconnects a base 414 and a neck 416. The body 412 has an outerwall 411 that defines an interior chamber 418 for storing apredetermined medicament and a central axis 413 for vial assembly 400.

Unlike vial 300, in which base 314 and body 312 are formed as a unit,the base 414 and the body 412 of storage vial 410 are formedindependently. Base 414 includes an inner surface 422 which is adaptedand configured for engagement with an axially depending flange 424 ofstorage vial 410. The base 414 can be engaged with the body 412 by meansof a press-fit relationship, adhesion, ultrasonic welding or any otherjoining technique. Due to its width, and as with the base of the vial300 as described above, the base 414 increases the vertical stability ofvial assembly 400 when placed on a horizontal surface.

With continuing reference to FIG. 15, in the embodiment shown herein,stopper member 430 has an annular groove 434 defined in outer periphery432. When stopper member 430 is inserted into the mouth 420 of storagevial 410, an annular recess is formed between stopper member 430 and theneck 416 of storage vial 410. Securing ring 450 is formed in this recesspreferably in the manner hereinafter described.

Referring now to FIGS. 16A and 16B, a representative process for formingsecuring ring 450 is illustrated. As shown in FIG. 16A, vial body 412 isfirst placed within a cavity defined by lower mold assembly 460. Forease in manufacturing, base 414 has not yet been engaged with flange 424of vial body 412. Mold assembly 460 includes a bottom 462 and first andsecond sidewalls 464 and 466, respectively.

Stopper member 430 is then inserted into the mouth of vial body 412. Asnoted above with respect to FIG. 15, stopper member 430 has an annulargroove 434 defined in its outer periphery 432. When stopper member 430is inserted into the mouth of vial body 412, an annular recess is formedbetween stopper member 430 and the neck 416 of storage vial 410.Alternatively, to reduce the potential for particulate contamination,vial body 412 and stopper member 430 can be formed in side-by-side moldsin a clean room environment. The stopper member 430 can be inserted intothe mouth of the vial body 412 prior to the transfer out of the cleanroom environment and to mold assembly 460 thereby preventing particulatefrom accumulating in the interior chamber 418.

Next, as shown in FIG. 16b , upper mold element 468 is positioned overlower mold assembly 460. Securing ring 450 is then formed by injecting(indicated by the flow arrows) at least one of a thermoplastic andelastic material in liquefied form into the annular recess. During themolding process, and when the vial body is formed of a plastic material(as opposed to glass, for example) the temperature of the material usedto form securing ring 450 is sufficient to partially melt on contact theadjacent material of neck 416. Therefore, upon cooling, securing ring450 is partially fused with neck 416 so as to retain stopper member 430within the vial mouth. It should be noted that the fusion can beachieved by ultrasonic welding, by applying thermal energy or by anyother known technique for joining thermoplastics, elastics, or othermaterials employed.

A closure for a vial manufactured in accordance with the method detailedin FIGS. 16A and 16B includes a sealing ring formed by injectingliquefied ENGAGE™ polyolefin into the annular recess defined between thestopper and the vial neck at a temperature in excess of about 390° F.The stopper is made from a thermoplastic comprising a blend of ENGAGE™and DYNAFLEX™ in the manner described above. The temperature of theliquefied ENGAGE™ is sufficient to locally melt the thermoplasticstopper as well as the vial neck. Upon cooling of the materials, air maybe supplied to the interior chamber through an aperture drilled orotherwise formed in the bottom of the vial body. Applicant hasdetermined that the interior chamber may be pressurized in excess ofabout 80 psi without dislodging the closure formed by the stopper andsecuring ring from within the vial mouth.

Referring now to FIGS. 17A through 17C, a representative process formaking a vial assembly in accordance with the present disclosure isillustrated. Vial assembly 500 includes a storage vial 510, anover-molded stopper 530 and an over-molded base 580. Storage vial 510 isstructurally similar to storage vials 310 and 410 described above,except that storage vial 510 has both an open top and an open bottomend.

As with the vial 310 described above, and as shown in FIG. 15, the vial410 defines a diabolo or spool-like shape formed by the relativelylarger diameters D1 of the upper portion 417 and D3 of the base 415, andthe relatively smaller diameter D2 of the body 412 extending axiallybetween the upper portion and base.

As shown in FIG. 17A, storage vial 510 is first positioned within acavity partially defined by mold assembly 560. Mold assembly 560includes bottom portion 562, first and second sidewalls 564 and 566,respectively, and upper portion 568. Bottom portion 562 of mold assembly560 has a cylindrical mold insert 570 projecting therefrom and intostorage vial 510. An upper surface 572 of mold insert 570 is adapted andconfigured for defining a lower surface for over-molded stopper 530.Over-molded stopper 530 is formed by injecting at least one of athermoplastic and elastic material in liquefied form into the cavitydefined by the molding elements.

Upon the formation of stopper 530, the vial body 510 with over-moldedstopper 530 is removed from the mold. As shown in FIG. 17B, a basemember 514 is engaged with the bottom of storage vial 510 by any of themethods described above. Lastly, the assembled vial is positioned withina second mold assembly (not shown) and an over-molded base 580 is formedin a manner similar to the previously described over-molding process.

Referring now to FIG. 18, another vial assembly constructed inaccordance with a representative embodiment of the present disclosure isdesignated generally by reference numeral 600. Similarly to thepreviously described embodiments, vial assembly 600 includes a storagevial 610 and a stopper member 630. Storage vial 610 has a cylindricalbody 612, a snap-on base 614 and a neck 616. Body 612 defines aninterior chamber 618 for storing a predetermined medicament and acentral axis for vial assembly 600.

As described above, stopper member 630 includes an outer peripheralsurface 632 which is adapted and configured for engagement with the neck616 of storage vial 610. Peripheral surface 632 of stopper member 630provides a first primary seal for containing the predeterminedmedicament within the interior chamber of vial body. As can be seen, theneck 616 of the vial defines a pointed annular protuberance 617 thatprojects axially into the overlying stopper material to thereby furthereffectuate a hermetic seal between the stopper and vial. In contrast tothe previously described embodiments, vial assembly 600 further includesa locking or securing ring or locking ring 650 and a snap-off,tamper-resistant cover 640. Locking ring 650 has an outer peripheralflange 652 that defines a shoulder 654 on an inner surface thereof.Shoulder 654 is adapted and configured for interlocking engagement withlower surface 620 of neck 614. Locking ring 650 is made from arelatively flexible, non-metallic material, such as plastic.

During the assembly process, locking ring 650 is positioned over stoppermember 630. Locking ring 650 is pressed axially downward so as tocompress and retain stopper member 630 within the mouth of the vial. Theflexibility and configuration of flange 652 of the locking ring allowsthe flange to flex radially outward of outer peripheral surface 622 ofneck 614. Once shoulder 654 passes axially downward beyond lower surface620, the flange 652 flexes back and shoulder 654 and lower surface 620form a snap-fit, interlocking engagement. In a representativeembodiment, an annular recess is scored or otherwise formed in the outersurface of flange 652 after the locking ring 650 is engaged with neck614 of storage vial 610. As can be seen, locking ring 650 can not bedisengaged from neck 614 without breaking flange 652. This featurefunctions to prevent removal of the stopper and any tampering with thecontents of the vial without piercing the stopper.

Locking ring 650 defines a central aperture that allows stopper member630 to be accessed therethrough by a needle or like device.Tamper-resistant cover 640 is configured to overlie the central apertureof locking ring 650 and engage with locking ring 650, thereby protectingthe exposed stopper material. In the embodiment shown herein, cover 640is engaged with locking ring 650 by means of a press-fit similar to thatpreviously described for the locking ring 650. Cover 640 includes anouter peripheral flange 642 that defines a shoulder 655 on an innerdiameter thereof which is adapted for interlocking engagement withperipheral recess 656 associated with locking ring 650. Tamper-resistantcover 640 further defines on its underside a pointed annularprotuberance 657 that is pressed into engagement with the adjacentstopper material to thereby effectuate a hermetic seal between the cover640 and stopper 630. Preferably, tamper-resistant cover 640 cannot beremoved from the vial without breaking the cover, thus providing afurther tamper-resistant feature. Alternatively, this tamper-resistantfeature can be created by using ultrasonic welding, adhesion, or anyother connection technique to engage tamper-resistant cover 640 withlocking ring 650 so that once removed, cover 640 can not be re-engagedwith locking ring 650.

As may be recognized by those of ordinary skill in the pertinent artbased on the teachings herein, the vial may be made of glass, plastic,or a combination of glass and plastic. For example, the vial body may bemade of glass, whereas the base 614 may be made of plastic, and thelocking ring 650 and tamper-resistant ring may be made of plastic. Theplastic base and locking ring may be attached to the glass vial body inany of the numerous different ways described herein, including byover-molding the plastic component onto the glass component, bymechanical snap-fit or other interlocking engagement between the plasticcomponent and the glass component, or by adhesively joining the plasticcomponent to the glass component. In addition, in this embodiment of theinvention, the stopper may include a vulcanized rubber or otherinfusible base portion, and a thermoplastic or other thermally fusibleportion overlying the base portion that is thermally fusible in themanner described above. One advantage of this type of embodiment of thepresent invention, is that the medicament or other substance containedwithin the vial is exposed to, or stored in contact with only the glassand vulcanized rubber surfaces. Thus, this type of embodiment may beeasily used with medicaments or other substances that are were in thepast stored in glass vials with vulcanized rubber or like stoppers.

In FIGS. 22A, 22B and 22C, the cover 640 is illustrated in furtherdetail and includes a frangible portion 660 connected to the remainderof the cover by a plurality of radially-spaced frangible connections662. As can be seen, in order to access the resealable stopper 630 witha needle or like device, the frangible portion 660 must be flipped awayfrom the stopper with sufficient force to break the frangibleconnections 662 and thus permit release of the frangible portion 660therefrom. As can be seen, the cover 640 may define a peripheral rim 664that is engageable by a user's thumb, for example, to press and, inturn, break away the frangible portion 660. Once the frangibleconnections 662 are broken, the frangible portion 660 cannot bereattached, thus providing a tamper-proof feature. In addition, theannular protuberance 657 and associated portion of the cover overlyingthe stopper material within the central aperture of the locking ring 650further seals the stopper and interior portions of the vial from theambient atmosphere, and thus further prevents the exposure of ambientgases, vapors or other unwanted substances to either the stopper or thesubstances contained within the vial. For example, the cover 640 cansignificantly improve the vapor (or MVT) barrier provided by the stopperassembly and thereby increase the effective shelf-life of the substancescontained within the vial.

One of the advantages associated with the vial assembly 600, as well asvial assemblies 300, 400, and 500, is that they are configured to bespool-shaped or diabolo-shaped. As described above, the upper and lowerportions of the vial assemblies have outer peripheral surfaces which arepositioned radially outward of the central vial body. As a result,during the withdrawal of the medicament by the healthcare worker, thefingers that grasp the recessed vial body are protected and are lesslikely to be pierced by a needle that has slipped off of the stopper.

Configuring the vial assembly so as to be diabolo-shaped also improvesthe stability of the filled vials, as well as the handling of the vialsduring the sterilization and filling processes. A vial with a base thathas an outer peripheral surface positioned radially outward of thecentral vial body has a lower center of gravity than a traditional blowmolded vial of the same height with a base that does not protruderadially from the vial body. The protrusion of the upper and lowerportions beyond the outer diameter of the vial body also improves thehandling of the vial body or assembly by providing upper and lowershoulders which can be used to guide the vial during the handlingprocess and facilitate the use of automated handling equipment (e.g.,pick and place robotics).

A further advantage of the vial assemblies described herein is that thetamper-resistant covers may be hermetically sealed to the underlyinglocking members and/or the resealable stoppers to thereby seal thestoppers within the locking members and covers and with respect to theambient atmosphere. In accordance with one aspect of a preferredembodiment of the present invention, the overlying locking members andcovers can be formed of relatively rigid materials and/or of materialshaving relatively high resistances to moisture and vapor transmission incomparison to the material of the resealable stopper itself, in order tofacilitate preventing the loss of any medicament or other substancecontained within the vial or other container therethrough, or theingress of moisture or vapor into the vial or other container, during,for example, storage, transportation and/or product shelf life.

With reference to FIGS. 19 through 21, there is illustrated another vialassembly 700 constructed in accordance with inventive aspects of thepresent disclosure. Vial assembly 700 includes, among other features, aclosure assembly 735 and a vial body 710. Similar to the closureassembly of FIG. 18, closure assembly 735 is a three-piece assemblycomprising a stopper member 730, a locking or securing ring or cap 750and a tamper-resistant cover 740.

Unlike the closure assembly of FIG. 18, closure assembly 735 is formedpartially by a sequential molding process. More specifically, thestopper 730 (FIG. 20) and the locking ring 750 are formed as a unit by atwo-step molding process. The stopper 730 is first fabricated by anyknown molding process. As shown in FIG. 20, the outer periphery 732 ofstopper 730 includes an annular recess 736. Stopper 730 is then placedin a mold assembly and is used to define at least a portion of the innersurface 752 of locking ring 750. A thermoplastic or elastic is injectedinto the mold so as to form locking ring 750 having an annularprotrusion 754 that is engaged within the annular recess 736 of stopper730. Then, as shown in FIG. 19, the unitized stopper/locking ring isengaged with the open end of vial body 710 so as to seal interior cavity718.

Locking ring 750 includes an annular groove 756 formed along its outerperiphery. As shown in FIG. 19, tamper-resistant cover 740 includes anouter peripheral flange 744 depending therefrom. Flange 744 is slidablyengaged within groove 756 of locking ring 750 and secures cover 740 tolocking ring 750. When the tamper-resistant cover 740 is pressed intoengagement with locking ring 750, annular rib 738 of stopper 730 iscompressed by the bottom of the cover and a second hermetic seal isthereby formed. Accordingly, the tamper-resistant cover 740 forms ahermetic or gas-tight seal between the exterior surface of the stopperand the ambient atmosphere, thereby providing a further MVT barrierbetween the interior of the vial and the ambient atmosphere. As may berecognized by those of ordinary skill in the pertinent art based on theteachings herein, the material(s) and/or thickness of thetamper-resistant cover 740 and/or of the locking ring 750, or at leastthe portion(s) of the cover and/or locking ring that overly and seal theexposed surface(s) of the stopper, may be selected to control the MVTbarrier between the interior and exterior of the vial in the directionthrough the stopper.

The annular groove 756 formed along the outer periphery of locking ring750 also functions to reduce the likelihood of an accidental needlestick. In order to access stopper 730, for the purpose of removingmedicament from within interior chamber 718, cover 740 is disengagedfrom locking ring 750 exposing groove 756. If by chance the needle beingused to withdraw the medicament accidentally slips off of or relative tothe stopper 730, the needle will likely slide into annular groove 756rather than continue in a downward trajectory and potentially pierce thehand of the healthcare worker.

With continuing reference to FIGS. 19 and 20, cavity 734, which isdefined in the bottom of stopper 730, allows the upper portion of thestopper 730 to flex upon the application of force to annular rib 738 bycover 740. As a result, the lower portion of the stopper member isforced radially outward and the circumferential seal created between theouter periphery 732 of the stopper 730 and the vial body 710 isimproved. Additionally, the upper portion of stopper 730 is radiallycompressed as a result of the forces applied to annular rib 738, forminga hermetic or gas-tight seal between the tamper-resistant cover 740 andthe exposed surface of the stopper to thereby further seal the stopperfrom the ambient atmosphere and, if desired, further improve the MVTbarrier between the interior of the vial and the ambient atmosphere.

In FIGS. 23 through 28, another vial embodying the present invention isindicated generally by the reference numeral 800. The vial 800 issimilar in many respects to the vials described above with reference toFIGS. 14 through 23, and therefore like reference numerals preceded bythe numeral “8” are used to indicate like elements. The primarydifference of the vial 800 in comparison to the vials described above isthat the locking ring 850 is welded, such as by ultrasonic welding, tothe neck 816 of the vial body. In addition, the flip-top ortamper-resistant cover 840 is tack welded, such as by ultrasonicwelding, to the locking ring 850. As shown in FIGS. 24 and 28, thestopper 830 defines an annular flange 832, the neck 816 of the vial bodydefines a pointed annular protuberance 817 that projects into one sideof the stopper flange 832, and the locking ring 850 defines anotherannular protuberance 819 that projects into the opposite side of thestopper flange 832. Thus, the annular protuberances 817 and 819 definecontinuous, annular sealing surfaces that facilitate in effectuating agas-tight or hermetic seal between the stopper and vial body. Further,as shown in FIG. 24, the peripheral surface 832 forms an interferencefit with the interior of the valve body 810 to further effectuate agas-tight or hermetic seal between the stopper and vial body. The neck816 defines on its axial face a pointed annular protuberance 821 that isreceived within a corresponding annular recess 823 defined in theunderside of the locking ring 850. The annular protuberance 821 is fusedto the locking ring 850 within the annular recess 823 by ultrasonicwelding, for example, to thereby fixedly secure the locking ring to thevial body. In addition, the annular weld preferably defines a hermeticor gas-tight seal between the locking ring and vial body to furthereffectuate a gas-tight or hermetic seal between the interior of the vialand the ambient atmosphere. The locking ring 850 further defines on itsdistal end a plurality of discrete radially-extending protuberances 866received within corresponding recesses 868 formed within the undersideof the locking ring 840. The protuberances 866 are fused to the cover840 within the recesses 868 by, for example, ultrasonic welding, tothereby define a plurality of frangible connections between the cover840 and locking ring 850. Alternatively, as shown in FIG. 27,protuberances 866′ may be formed at the base of the flange 842 of thecover and may be fused within corresponding recesses 868′ formed withinthe annular recess 870 of the locking ring. As also shown in FIGS. 24,27 and 28, the base of the vial body defines a pointed annularprotuberance 815 that is received within a corresponding annular recessformed in the base 814 for fixedly securing the base to the body, suchas, for example, by ultrasonic welding.

In order to fill the vial 810, the stopper 830, locking ring 850, andbase 814 are assembled to the empty vial body, such as by ultrasonicwelding. Then, the empty vial is sterilized, such as by the applicationof gamma or other type of radiation thereto. Then, the sterilized, emptyvials are needle filled and thermally resealed, such as by laserresealing as described above. Then, the tamper-resistant cover 840 isassembled to the filled vial by fixedly securing the cover to thelocking ring 850, such as by ultrasonic welding as described above. Asshown typically in FIG. 24, the exterior surface of the stopper 830 mayform an interference fit with the interior surface of thetamper-resistant cover to further effectuate a gas-tight or hermeticseal between the cover and stopper to, in turn, form a further MVTbarrier between the interior of the vial and the ambient atmospherethrough the cover. If desired, a peripheral seal may be formed betweenfrusto-conical portion 870 of the locking ring and the underside of thetamper-resistant cover 840 by forming an annular seal at 866,868 by, forexample, ultrasonic welding, to form the hermetic or gas-tight sealbetween the stopper and the ambient atmosphere and, in turn, form thedesired MVT barrier. In order to use the vial, the tamper-resistantcover 840 is removed by gripping with, for example, a thumb, theperipheral edge 843 of the cover, and pushing the cover upwardly orsubstantially axially away from the locking ring to, in turn, break thefrangible connections 866, 868 or 866′, 868′ and release the cover, or afrangible portion thereof, from the locking ring to expose theunderlying stopper. As may be recognized by those of ordinary skill inthe pertinent art based on the teachings herein, the tamper-resistantcover and/or the frangible portion thereof may taken any of numerousdifferent shapes and/or configurations that are currently or laterbecome known for performing the function of the tamper-resistant coveras described herein.

In FIGS. 29 through 31, another vial embodying the present invention isindicated generally by the reference numeral 900. The vial 900 issimilar in many respects to the vials described above with reference toFIGS. 14 through 28, and therefore like reference numerals preceded bythe numeral “9” are used to indicate like elements. The primarydifference of the vial 900 in comparison to the vials described above isthat the locking ring 950 is snap-fit to the vial body 910, and thelocking ring 950 defines the neck 916 of the vial. As can be seen, thelocking ring 950 defines a peripheral flange forming the neck 916 andfurther defines on its interior edge an annular recess 968 for receivingtherein an annular protuberance 966 formed on the tamper-resistant cover940. As can be seen, the interior edge of the annular flange 916 leadinginto the recess 968 defines a chamfered surface, and the leading edge ofthe annular protuberance 966 of the cover also is chamfered to allow theprotuberance to be snapped into, or otherwise fixedly received withinthe recess, but to prevent removal of the cover therefrom. Similarly,the locking ring 950 defines on its inner diameter an annularprotuberance 921 that is snapped into, or otherwise fixedly receivedwithin a corresponding annular recess 923 formed on the exterior of thevial body to fixedly secure the cover to the vial body. In thisembodiment, the base 914 of the vial body is formed integral with theremainder of the vial body in order to reduce the number of parts;however, if desired, the base 914 can be made as a separate part that issnap-fit or otherwise attached to the vial body.

As shown typically in FIG. 31, the tamper-resistant cover 940 defines acentrally-located frangible portion 960, an inwardly depending annularprotuberance 963 that engages the exposed surface of the stopper 930 andforms a hermetic or gas-tight seal therebetween, and a frusto-conicalportion 965 that is formed on its outer end contiguous to the annularprotuberance 963 and preferably forms a gas-tight or hermetic sealtherebetween. As shown in FIGS. 30 and 31, a plurality of frangibleconnections 962 are angularly spaced relative to each other and extendbetween the frangible portion 960 and a substantially dome-shaped coverbody 941 to allow removal of the frangible portion and access to theunderlying stopper 930. As indicated by the arrow in FIG. 32, thefrangible portion 960 of the cover is pressed downwardly by, forexample, a user's finger to slightly depress the underlying stoppermaterial and, in turn, break the frangible connections 962. Onceremoved, the frangible portion 960 cannot be reconnected to therebyprovide a tamper-proof feature. Thus, prior to removing the frangibleportion 960 of the tamper-resistant cover 940, the frangible portion960, along with its annular protuberance 963, and the frusto-conicalportion 965 of the locking ring 950, form a substantially gas-tight orhermetic seal between the stopper and ambient atmosphere, and thusprovide a further MVT barrier between the interior of the vial andambient atmosphere in the direction through the stopper. If desired, orotherwise deemed necessary to further obtain a desired MVT barrier, thefrusto-conical portion 965 and peripheral flange 916 may form acontinuous solid barrier, as indicated in broken lines in FIG. 29 (i.e.,without any openings), to completely seal the stopper from the ambientatmosphere.

Turning to FIGS. 32 through 36, a plurality of the diabolo shaped vials610 of the present invention are shown mounted within a sterile fillingmachine that needle fills and laser reseals the vials as disclosed inco-pending U.S. Provisional Patent Application Ser. No. 60/484,204,filed Jun. 30, 2004, and incorporated by reference above. As can beseen, each vial 610 does not include the tamper-resistant cover 640(FIG. 18) during the needle filling and laser resealing process, butrather the tamper-resistant covers are secured to the vials after needlefilling and laser resealing. As may be recognized by those of ordinaryskill in the pertinent art based on the teachings herein, although thevials 610 are shown mounted within the sterile filling machine, any ofthe other vials described herein or otherwise embodying the features ofthe invention equally may be filled and sealed in the illustratedsterile filling machine. The sterile filling machine includes a sterileenclosure (not shown), a laminar flow source (not shown) that provides asubstantially laminar flow of sterile air of other gas over the vialsbeing transported within the enclosure, and as shown in FIGS. 33-36, atransport system comprising in the illustrated embodiment a plurality ofstar wheels 1010, and associated guides 1012 spaced adjacent to theperiphery of each star wheel 1010 for supporting the vials 610therebetween.

As shown in FIGS. 33-36, each of the star wheels 1010 has a plurality ofrecesses 1014 along its peripheral surface that are adapted to receivethe mid-portions of the vials 610. One or more of the star wheels mayhave a saw-tooth like periphery that reduces the likelihood of jammingagainst vials as they are received, for example, from a turntable andinfeed channel into the star wheels. In such embodiment, the peripheryof the star wheel defines a plurality of teeth, wherein each tooth has apointed end, and each two successive teeth form a respective one of therecesses adapted to receive a vial. In this embodiment, the teeth and/orrecesses are shaped and/or dimensioned such that the portion of thetooth that is substantially upstream and adjacent to the point defines aseat in which a respective vial rests. Also in this embodiment, the seatdefines a surface that pushes against the container. Other designs mayof course also be employed. If desired, the recesses 1014 of one or morestar wheels may be provided with vacuum ports which are selectivelyconnected to a vacuum source (not shown) to thereby allow the starwheels to carry and release vials as appropriate.

As shown best in FIGS. 32-35, a needle fill manifold 1016 is disposed ata first position along the periphery of the star wheel 1010 in a needlefilling station of the sterile filling machine. The needle fill manifold1016 holds a plurality of needles, e.g., four needles 1018, 1020, 1022and 1024, which are used to deliver medicament or other substances intothe sealed vials. The needle manifold 1016 is drivingly mounted suchthat each needle is movable into and out of engagement with theresealable stoppers to pierce the stoppers and fill the vials with amedicament or other substance to be contained therein, and to thenwithdraw the needle upon filling the vial. Providing multiple needlesmakes it possible to fill multiple vials concurrently. Each of theneedles is in flow communication with a respective flexible tube 1026,1028, 1030 and 1032 that connects the respective needle 1018, 1020, 1022and 1024 to a respective medicament or other substance source (notshown) through a respective one of a plurality of pumps (not shown). Themedicament source may be located inside the filling machine or outsideof the filling machine.

As shown in FIGS. 33-35, the needle fill manifold 1016 is mounted on apair drive shafts 1034 that are drivingly connected to a suitable drivesource (not shown) driving the needle manifold, and thus the bank ofneedles mounted on the manifold, into and out of engagement with theresealable stoppers of the vials mounted in the needle filling station,as indicated by the arrow “a” shown typically in FIG. 33. Although notshown, a bellows may encase the base of each shaft to seal the movableparts of the shafts. As shown best in FIG. 32, the needle manifold 1016further includes a base 1036, a plurality of needle mounts 1038 spacedrelative to each other and defining laminar flow apertures 1040therebetween, and a clamp 1042 that is fixedly secured by fasteners 1044(FIG. 33) to the base 1036 to, in turn, secure the needles to themanifold. As shown in FIG. 32, each needle includes a mounting flange1046 that is slidably received within an aperture formed in therespective needle mount 1038, and is fixed in place upon securing theclamp 1042 to the base 1036. Alignment pins 1048 project outwardly fromthe front face of the base 1036 and are received within correspondingapertures formed in the clamp 1042 to ensure proper alignment of theclamp and needles on the manifold. As shown in FIG. 35, the a mountingplate 1050 is fixedly secured to the ends of the drive shafts 1034, 1034and is movable therewith. Alignment pins (not shown) extend between thebase 1036 of the needle manifold 1016 and the drive plate 1050 to ensureproper alignment of the needle manifold, and thus the needles, on thedrive plate. A pair of thumb screws 1052 are threadedly received throughopposite ends of the base 1036 of the manifold to releasably secure themanifold to the drive plate 1050.

As shown in FIG. 36, a laser sealing and infrared (IR) sense manifold1054 is disposed at a second position along the periphery of the starwheel 1010, downstream of the needle fill manifold 1016. As showntypically in FIG. 36, the laser sealing and infrared (IR) sense manifold1054 holds a plurality of laser optics assemblies (e.g., four laseroptic assemblies 1056, 1058, 1060 and 1062), along with a plurality ofIR sensors (e.g., four IR sensors 1064, 1066, 1068 and 1070). The laseroptic assemblies are adapted to provide a laser beam to reseal theresealable stoppers on the vials after needle filling. Each of theplurality of laser optic assemblies is mounted at a respective locationnear the periphery of the star wheel 1010 for transmitting a respectivelaser beam onto a respective resealable stopper to heat seal the needleaperture in the resealable stopper. Each of the laser optic assemblies1056, 1058, 1060 and 1062 is connected to a respective fiber optic cablethat connects the respective optic assembly to a respective laser source(not shown). Providing multiple fiber optic assemblies makes it possibleto reseal multiple vials concurrently. In this embodiment, each of theplurality of IR sensor assemblies 1064-1070 is mounted at a respectivelocation near the periphery of the star wheel 1010. Preferably, thelaser sources (not shown) are mounted outside of the enclosure to enablerepair and/or replacement of the laser sources without having to openthe enclosure and/or otherwise risk contamination of the sterileenclosure. The IR sensors 1064-1070 detect the temperature of the needlepenetration region of the resealable stopper achieved during laserresealing, and therefore can be used to determine whether the stopperwas sufficiently reheated to achieve resealing. Each of the IR sensors1064-1070 is connected to a respective IR sensor module (not shown).Providing multiple IR sensors enables the sterile filling machine tosense the temperature of multiple vials concurrently, for example, asthey are being resealed.

As described above, each laser source transmits a predeterminedwavelength of laser radiation at about 980 nm, and the predeterminedpower of each laser is preferably less than about 30 Watts, andpreferably less than or equal to about 10 Watts, or within the range ofabout 8 to about 10 Watts. In the illustrated embodiment, each lasersource is a semi-conductor diode laser that outputs at about 15 Watts,and is fiber-optically coupled through a fiber-optic cable to respectivecollimating lens mounted over the vials within the interior of thefilling unit. The laser and IR sensor manifold 1054 includes a tintedenclosure 1072 including a plurality of tinted glass or translucent ortransparent plastic panels that surround the lasers on four sides tofilter out potentially harmful radiation generated by the laser beams.Capacitor sensors (not shown) also may be provided along the peripheryof the star wheel 1010, downstream of the needle fill manifold 1016 inorder to sense whether each vial received the medicament or othersubstance to be contained therein and to reject the vial if defective.

In the operation of the sterile filling machine, the star wheel 1010transports the vials 610 along the guide 1012 in the manner illustrated.The star wheel 1012 is indexed four positions and then paused for amomentary dwell. During the dwell, the needle manifold 1016 is drivendownward so as to drive the four needles 1018-1024 through theresealable stoppers on the four vials beneath the needle manifold.Medicament or other substance is thereafter delivered by the pumpthrough the needles and into the interior chambers of the vials, and themanifold is then driven up to thereby retract the four needles 1018-1024from the four stoppers. In one embodiment, the needles are initiallywithdrawn at a relatively slow speed to allow the vials to fill“bottom-up”; then, when the vials are filled, the needles are withdrawnat a relatively faster speed to quickly remove the needles and decreasesoverall cycle time. As shown in FIGS. 33-35, the diabolo or spool-likeshape of the vials facilitates the ability to transport the vials on thestar wheels or other conveying system, and further, the diabolo shapesupport the vials and prevents axial movement of the vials duringinsertion and withdrawal of the needles during filling. The mid-portionof each vial is secured within the recess of the star wheel or otherconveying mechanism, the relatively larger diameter upper portion ofeach vial prevents axial downward movement of the vial upon insertingthe needle into the resealable stopper of the vial by engaging the uppersurface of the star wheel and/or guide, and the relatively largerdiameter base portion of the vial prevents upward axial movement of thevial upon withdrawal of the needle from the resealable stopper byengaging the underside of the star wheel and/or guide.

Also during the dwell, the four laser optic assemblies 1056-1062 deliverlaser energy to the resealable stoppers on the four vials beneath thelaser and IR manifold to reseal the stoppers. As the resealable stoppersare heated by the laser energy, the four IR sensors 1064-1070 detect thetemperature of each stopper, so as to be able to determine whether eachstopper was heated sufficient to cause resealing. After the dwell, theprocess is repeated, i.e., the star wheels index another four positionsand then dwell again so that the next four vials are filled and fourmore vials are resealed.

After resealing, the vials are transferred to the another star wheel(not shown), which employs the vacuum ports in its recesses to retaineach vial as it is transported. If a vial was successfully filled andsealed, then the star wheel transports that vial until reaching adischarge guide, at which point the vacuum to the associated vacuum portis selectively removed and the vial is transferred to the dischargeguide. The discharge guide transports the vial to a bin (not shown) ofsuccessfully filled and sealed containers. If a vial was notsuccessfully filled and sealed, then the star wheel transports that vialuntil it reaches another star wheel, at which point the vacuum to theassociated vacuum port is selectively removed and vacuum is applied tothe respective vacuum port on the other star wheel, thereby transferringthe vial to the other star wheel for disposal with any other defectivevials.

In FIGS. 37-48, a module for needle filling and laser resealing thevials is indicated generally by the reference numeral 2000. The needlefilling and laser resealing module 2000 is similar in many respects tothe needle manifold and laser and IR sensor manifold described above,and therefore like reference numerals preceded by the numeral “2”instead of the numeral “1” are used to indicate like elements. One ofthe primary differences of the module 2000 in comparison to themanifolds described above, is that the module 2000 permits both needlefilling and laser resealing in the same module. Further, if desired, themodule 2000 can include an e-beam or other suitable radiation orsterilization source to further ensure sterilization of the vials andfilling needles, as described further below.

The module 2000 may be mounted within any of numerous different types ofsterile enclosures, and may be used with any of numerous different typesof conveying systems for conveying the vials through the module. Ifdesired, the sterile enclosure may include a laminar flow source asdescribed in the above-mentioned co-pending patent application.Preferably, the transport system through the module is substantiallylinear, and includes a guide 2010 defining an axially elongated aperture2014 extending therethrough. As shown in FIGS. 39 and 40, the axiallyextending aperture 2014 is dimensioned to slidable receive therein themid-portions of the diabolo-shaped vials, to support on the upperopposing surfaces of the guide 2010 the relatively larger diameter upperportion of each vial, and if desired, to support against the opposinglower surfaces of the guide the relatively larger diameter base portionof each vial. In one embodiment of the present invention illustrated inFIG. 43, the transport system comprises a screw-type drive including alead screw 2015 defining a helical groove 2017 forming the recesses forreceiving the vials 610. A motor 2019 is drivingly connected to one endof the lead screw and rotatably drives the screw as indicated by thearrow “b” to, in turn, axially drive the vials 610 through the manifold2000. The motor 2019 is electrically connected to a control unit (notshown) to precisely control the starting, stopping and speed of thescrew, and to coordinate same with the actuation of the needle manifoldand laser sources. As may be recognized by those of ordinary skill inthe pertinent art based on the teachings herein, the transport systemmay include any of numerous different structures for driving the vialsthrough the manifold, including, for example, other types of conveyors,that are currently, or later become known, for performing this function.

The needle fill manifold 2016 is mounted on a pair drive shafts 2034that are drivingly connected through a common drive shaft 2035 (FIG. 42)to a suitable drive source (not shown) for driving the needle manifold,and thus the bank of needles 2018 (only one shown) mounted on themanifold, into and out of engagement with the resealable stoppers of thevials received within the guide 2010 of the manifold. Although notshown, a bellows may encase the base of each shaft to seal the movableparts of the shafts. The needle manifold 2016 includes a base 2036, aplurality of needle mounts 2038 spaced relative to each other, and aclamp 2042 that is fixedly secured by fasteners (not shown) to the base2036 to, in turn, secure the needles to the manifold. If desired,laminar flow apertures may be formed between the needle mounts 2038 toallow the flow of sterile air or other gas therethrough and over thesides of the needles. Each needle includes a mounting flange 2046 thatis slidably received within an aperture formed in the respective needlemount 2038, and is fixed in place upon securing the clamp 2042 to thebase 2036. Providing multiple needles makes it possible to fill multiplevials concurrently. Each of the needles is in flow communication with arespective flexible tube 2026 that connects the respective needle 2018to a respective medicament or other substance source (not shown) througha respective one of a plurality of pumps (not shown). The medicamentsource may be located inside the filling machine or outside of thefilling machine.

As shown typically in FIG. 41, alignment pins 2039 may be provided onthe clamp 2042 and received within corresponding pin holes 2041 formedon the base 2036 to ensure proper alignment of the clamp and needles onthe manifold. A mounting plate 2050 is fixedly secured to the ends ofthe drive shafts 2034, 2034 and is movable therewith. The drive plate2050 defines a mounting surface 2053 that is received withincorresponding mounting grooves 2055 formed within the base 2036 of themanifold to mount and align the manifold on the drive plate. Alignmentpins (not shown) may extend between the base 2036 of the needle manifold2016 and the drive plate 2050 to ensure proper alignment of the needlemanifold, and thus the needles, on the drive plate. A locking clamp 2052is pivotally mounted on the drive plate 2050 and is movable between anopen position to either release the manifold from, or attach themanifold to the drive plate, as shown in FIG. 37, and a closed positionfixedly securing the manifold to the drive plate, as shown in FIG. 38.Alternatively, as shown in FIGS. 40A-40C, fasteners 2052′ may beemployed to secure the manifold to the drive plate, instead of theclamp. As may be recognized by those or ordinary skill in the pertinentart based on the teachings herein, any of numerous different clamps orfastening mechanisms that are currently known, or later become known,equally may be employed to secure the manifold to the drive plate.

The module 2000 further includes a laser sealing and infrared (IR) sensemanifold 2054 that is radially spaced adjacent to the needle manifold2036 for laser sealing the pierced stoppers immediately following needlefilling and withdrawal of the needles therefrom. As shown typically inFIG. 42, the laser sealing and infrared (IR) sense manifold 2054 holds aplurality of laser optics assemblies (e.g., five laser optic assemblies2056, 2058, 2060, 2062 and 2063), along with a plurality of IR sensors(e.g., five IR sensors 2064, 2066, 2068, 2070 and 2071). Note thatalthough only four laser optic assemblies and associated IR sensors areshown in FIG. 42 for simplicity, five laser optic assemblies andassociated IR sensors are shown in FIG. 43. The laser optic assembliesare adapted to provide a laser beam to reseal the resealable stoppers onthe vials after needle filling. Each of the plurality of laser opticassemblies is mounted at a respective location adjacent to the guide2010 for transmitting a respective laser beam onto the resealablestopper of a respective vial 610 to heat seal the needle aperture in theresealable stopper. In addition, each laser optic assembly is alignedwith a respective needle 2018 on the needle manifold 2016 to seal thelocation of the resealable stopper pierced by the respective needle.Each of the laser optic assemblies 2056-2063 is connected to arespective fiber optic cable that connects the respective optic assemblyto a respective laser source (not shown). As can be seen, providingmultiple fiber optic assemblies makes it possible to reseal multiplevials concurrently. In this embodiment, each of the plurality of IRsensor assemblies 2064-2071 is mounted adjacent to, and aligned with arespective laser optic assembly and needle 2018 on the needle manifold2016. Preferably, the laser sources (not shown) are mounted outside ofthe sterile enclosure of the needle filling machine within which themodule 2000 is mounted to enable repair and/or replacement of the lasersources without having to open the enclosure and/or otherwise riskcontamination of the sterile enclosure. The IR sensors 2064-2071 detectthe temperature of the needle penetration region of the resealablestopper achieved during laser resealing, and therefore can be used todetermine whether the stopper was sufficiently reheated to achieveresealing. Each of the IR sensors 2064-2071 is connected to a respectiveIR sensor module (not shown). Providing multiple IR sensors enables thesterile filling machine to sense the temperature of multiple vialsconcurrently, for example, as they are being resealed.

As described above, each laser source transmits a predeterminedwavelength of laser radiation at about 980 nm, and the predeterminedpower of each laser is preferably less than about 30 Watts, andpreferably less than or equal to about 10 Watts, or within the range ofabout 8 to about 10 Watts. In the illustrated embodiment, each lasersource is a semi-conductor diode laser that outputs at about 15 Watts,and is fiber-optically coupled through a fiber-optic cable to acollimating lens of the respective laser optic assembly. If desired, themodule 2000 can be enclosed, or partially enclosed within a tintedenclosure (not shown) including a plurality of tinted glass ortranslucent or transparent plastic panels that surround the laser opticassemblies on four sides to filter out potentially harmful radiationgenerated by the laser beams. In addition, capacitor sensors (not shown)may be provided downstream of the module 2000 in order to sense whethereach vial received the medicament or other substance to be containedtherein and to reject the vial if defective.

In the operation of the module 2000, the drive motor 2019 is rotatablydriven in the direction of the arrow “b” to rotate the lead screw 2015and, in turn, transport the vials 610 along the guide 2012 in the mannerillustrated, for example, in FIG. 43. In the exemplary module of FIG.43, the module includes five needles, five laser optic assemblies andfive IR sensors, thus permitting the needle filling and laser resealingof five vials at one time. Accordingly, the lead screw 2015 is indexedfive positions and then paused for a momentary dwell. As may berecognized by those or ordinary skill in the pertinent art based on theteachings herein, the module 2000 may include any desired number ofneedles, laser optic assemblies, and/or sensors. In addition, ifdesired, the lasers and sensors may be mounted within the moduledownstream of the needle manifold, to allow simultaneous filling andsealing of different vials, and thereby possibly increase the overallthroughput of the module. During the dwell, the needle manifold 2016 isdriven downward so as to drive the needles 2018 through the resealablestoppers on the vials beneath the needle manifold. Medicament or othersubstance is thereafter delivered by the pumps (not shown) through theneedles and into the interior chambers of the vials, and the manifold isthen driven up to thereby retract the needles 2018 from the stoppers. Inone embodiment, the needles are initially withdrawn at a relatively slowspeed to allow the vials to fill “bottom-up”; then, when the vials arefilled, the needles are withdrawn at a relatively faster speed toquickly remove the needles and decrease overall cycle time. As can beseen, the diabolo or spool-like shape of the vials facilitates theability to transport the vials in the conveying system, and further, thediabolo shape supports the vials and prevents axial movement of thevials during insertion and withdrawal of the needles during filling. Themid-portion of each vial is secured within the aperture 2014 of theguide 2010, the relatively larger diameter upper portion of each vialprevents axial downward movement of the vial upon inserting the needleinto the resealable stopper of the vial by engaging the upper surface ofthe guide, and the relatively larger diameter base portion of the vialprevents upward axial movement of the vial upon withdrawal of the needlefrom the resealable stopper by engaging the underside of the guide.

Also during the dwell, and following withdrawal of the needles from theresealable stoppers, the laser optic assemblies 2056-2063 deliver laserenergy to the resealable stoppers on the vials to reseal the stoppers.As the resealable stoppers are heated by the laser energy, the IRsensors 2064-2071 detect the temperature of each stopper, so as to beable to determine whether each stopper was heated sufficient to causeresealing. After the dwell, the process is repeated, i.e., the leadscrew indexes another five positions and then dwells again so that thenext five vials can be filled and resealed.

As shown in FIG. 44, the module 2000 may be mounted in a sterileenclosure wherein the transport system includes an endless conveyor 2076and carriers 2078 mounted on the endless conveyor 2076 for transportingthe vials 610 through the module 2000. An infeed conveyor 2080 feeds thesealed, empty vials onto the carriers 2078 of the endless conveyor 2076.Then, the endless conveyor 2076 feeds the vials through the module 2000in the same manner, or in a manner similar to that described above.After the vials are filled and resealed in the module 2000, they aredispensed onto an outlet conveyor 2082. As may be recognized by those ofordinary skill in the pertinent art based on the teachings herein, theconveyers 2076, 2080 and 2082 and/or the components thereof may take theform of any of numerous different conveyors or conveyor components thatare currently, or later become known for performing the functions of oneor more of these conveyors or conveyor components.

As shown in FIG. 42, the module 2002 further includes an axiallyelongated port 2084 located on an opposite side of the needle manifold2016 relative to the laser optic assemblies and sensors for mountingtherein an e-beam unit 2086 that transmits an e-beam into theaxially-elongated chamber 2088 of the module and, in turn, sterilizesthe surfaces of the vial and the needle surfaces within the chamber. Thee-beam assembly, including the e-beam source, the chamber for containingthe e-beam, and the conveyor for conveying the vials through the e-beamchamber, may be the same as, or similar to that disclosed in co-pendingU.S. patent application Ser. No. 10/600,525, filed Jun. 19, 2003,entitled “STERILE FILLING MACHINE HAVING NEEDLE FILLING STATION WITHINE-BEAM CHAMBER,” and U.S. Provisional Patent Application Ser. No.60/390,212, entitled “STERILE FILLING MACHINE HAVING NEEDLE FILLINGSTATION WITHIN E-BEAM CHAMBER,” filed Jun. 19, 2002, each of which ishereby expressly incorporated by reference as part of the presentdisclosure. As described in these co-pending patent applications, thee-beam unit may be any of numerous different types of e-beam units orsources that are currently, or later become known, for performing thefunction of the e-beam unit described herein.

E-beam radiation is a form of ionizing energy that is generallycharacterized by its low penetration and high dose rates. The electronsalter various chemical and molecular bonds upon contact with an exposedproduct, including the reproductive cells of microorganisms, andtherefore e-beam radiation is particularly suitable for sterilizingvials and other containers for medicaments or other sterile substances.An e-beam source produces an electron beam that is formed by aconcentrated, highly charged stream of electrons generated by theacceleration and conversion of electricity. Preferably, the electronbeam is focused onto a penetrable surface of each vial for piercing bythe respective needle. For example, in one embodiment, the electron beamis focused onto the upper surface of the resealable stopper to sterilizethe penetrable surface of the stopper prior to insertion of the fillingneedle therethrough. In addition, reflective surfaces may be mounted onopposite sides of the conveyor relative to each other to reflect thee-beam, and/or the reflected and scattered electrons, onto the sides ofthe vials to facilitate sterilization of these surfaces of the vial, ifnecessary. Alternatively, or in combination with such reflectivesurfaces, more than one e-beam source may be employed, wherein eache-beam source is focused onto a respective surface or surface portion ofthe vials or other containers to ensure sterilization of each surfacearea of interest. In some embodiments, the current, scan width, positionand energy of the e-beam, the speed of the transport system, and/or theorientation and position of any reflective surfaces, are selected toachieve at least about a 3 log reduction, and preferably about a 6 logreduction in bio-burden testing on the upper surface of the vial'sresealable stopper, i.e., the surface of the stopper defining thepenetrable region that is pierced by a respective filling needle to fillthe vial. In addition, as an added measure of caution, one or more ofthe foregoing variables also are preferably selected to achieve at leastabout a 3 log reduction on the sides of the vial, i.e., on the surfacesof the vial that are not pierced by the needle during filling. Inaddition, the e-beam may be directed onto the needles prior to entrythrough the resealable stoppers, or at least the portions of the needlesthat contact the stoppers, to further ensure sterilization of theneedles and vials. These specific levels of sterility are onlyexemplary, however, and the sterility levels may be set as desired orotherwise required to validate a particular product under, for example,United States FDA or applicable European standards, such as theapplicable Sterility Assurance Levels (“SAL”).

Turning to FIGS. 45-48, another vial embodying the present invention isindicated generally by the reference numeral 2200. The vial 2200 issimilar in many respects to the vial 900 described above with referenceto FIGS. 29-31, and therefore like reference numerals preceded by thenumeral “22” instead of the numeral “9” are used to indicate likeelements. With reference to FIG. 45, a primary difference of the vial2200 in comparison to the vial 900 described above is that thefrusto-conical or innermost edge 2265 of the locking ring 2250 is spacedrelatively inwardly to, in turn, permit a filling needle 2018 to piercethe resealable stopper 2230 at an acute angle “D” relative to the axisof the vial and in a peripheral portion of the penetrable region 2231 ofthe stopper. One advantage of this configuration is that, as shown inFIG. 47, the penetrated and laser (or otherwise thermally) resealedportion 2231 of the stopper is located on a marginal or peripheralportion of the region 2231 of the stopper, and thus can be concealedunder an inner edge 2233 of the tamper-resistant cover 2240 when thefrangible portion 2260 of the tamper-resistant cover is removed in use,as described further below.

As can be seen, the locking ring 2250 defines a peripheral flangeforming the neck 2216 and further defines on its interior edge anannular recess 2268 for receiving therein an annular protuberance 2266formed on the tamper-resistant cover 2250. The interior edge of theannular flange 2216 leading into the recess 2268 may define a chamferedsurface, and the leading edge of the annular protuberance 2266 of thecover also may be chamfered to allow the protuberance to be snappedinto, or otherwise fixedly received within the recess, but to preventremoval of the cover therefrom. Similarly, the locking ring 2250 defineson its inner diameter an annular protuberance 2221 that is snapped into,or otherwise fixedly received within a corresponding annular recess 2223formed on the exterior of the vial body 2210 to fixedly secure thelocking ring 2250 to the vial body. In this embodiment, the base 2214 ofthe vial body 2210 is formed integral with the remainder of the vialbody in order to reduce the number of parts; however, if desired, thebase 2214 can be made as a separate part that is snap-fit or otherwiseattached to the vial body.

As shown in FIGS. 47 and 48, the tamper-resistant cover 2240 defines acentrally-located frangible portion 2260, and an inwardly dependingannular protuberance 2263 that engages the exposed surface of thestopper 2230 and, if desired, may form a hermetic or gas-tight sealtherebetween. As shown in FIGS. 47 and 48, a plurality of frangibleconnections 2262 are angularly spaced relative to each other and extendbetween the frangible portion 2260 and a substantially dome-shaped coverbody 2241 to allow removal of the frangible portion and access to theunderlying stopper 2230. The frangible portion 2260 of the cover ispressed downwardly by, for example, a user's finger, to slightly depressthe underlying stopper material and, in turn, break the frangibleconnections 2262. Once removed, the frangible portion 2260 cannot bereconnected to thereby provide a tamper-proof feature. Thetamper-resistant cover 2240 further includes a second downwardlydepending protuberance 2235 located adjacent to the first protuberance2263 and in engagement with the exposed stopper to form a hermetic orgas-tight seal therebetween. If desired, the first and second annularprotuberances 2263 and 2235, respectively, may be formed contiguous witheach other to, in turn, form a gas-tight or hermetic seal therebetween,and thereby increase the MVT barrier of the vial in the directionthrough the stopper.

As indicated in FIG. 45, the vial 2200 may be filled in, for example, aneedle filling and laser resealing module as described above. However,one difference enabled by the vial 2200 is that the needle 2018 isinserted into the penetrable region 2231 of the resealable stopper 2230at an acute angle “D” relative to the axis of the vial, and in amarginal or outer peripheral portion of the penetrable region adjacentto the inner edge 2265 of the locking ring 2250. As can be seen incomparison to the locking ring 950 described above in connection withFIG. 29, the inner edge 2265 of the locking ring 2250 is spaced radiallyoutwardly to, in turn, expose the marginal portion of the penetrableregion 2231 of the stopper and permit same to be penetrated by theneedle 2018 at the acute angle “D”. One advantage of penetrating thestopper 2230 with the needle 2018 at the acute angle D, is that thefluid injected by the needle is directed onto the side wall of the vialbody 2210 substantially at the acute angle, as indicated by the arrow“E” in FIG. 45, and thus facilitates creating a laminar flow, orsubstantially laminar flow of fluid into the vial. This type of flowfacilitates in preventing the formation of bubbles or like turbulenteffects upon filling the vial with fluid, and thus permits the vials tobe filled more quickly and/or otherwise in a more desirable manner. Asmay be recognized by those of ordinary skill in the pertinent art basedon the teachings herein, the acute angle “D” may be created by orientingthe needles on the needle manifold at an acute angle relative to theaxis of the vial, or by orienting the axes of the vials in the fillingstation at an acute angle relative to the axes of the needles, or acombination of both. In the illustrated embodiment, the angle “D” iswithin the range of about 30° to about 45°; however, these angles areonly exemplary, and may be changed as desired to obtain the desired flowand/or filling characteristics, or otherwise as desired to meet therequirements of a particular application.

Another advantage of this embodiment of the present invention is thatthe penetrated/resealed portion of the stopper may be visually concealedfrom the end user throughout the use of the vial. As shown typically inFIG. 47, the needle hole, and thus the resealed portion 2231 of thestopper, is concealed under the inner edge portion 2233 of thetamper-resistant cover 2240. Accordingly, upon removing the frangibleportion 2260 of the tamper-resistant cover 2240 to access with a syringethe contents of the vial, the underlying and visually exposed portion ofthe stopper 2230 does not include the resealed portion 2231, and thusmay be considered more aesthetically desirable or pleasing than havingthe resealed portion visually exposed.

As may be recognized by those skilled in the pertinent art based on theteachings herein, numerous changes and modifications may be made to theabove-described and other embodiments of the present application withoutdeparting from the inventive aspects disclosed herein. For example, theresealable portion may be integrally molded with a base such as byinsert molding, the resealable portion may be fused or otherwise meltedto a base, or the resealable portion may be sequentially molded to abase. Alternatively, the resealable stopper may be formed of only onematerial, i.e., the resealable portion with the infusible base or otherinfusible layer, may be formed with multiple layers, wherein some or allof the layers are thermally resealable. Thus, the resealable stopper maybe made of any of numerous different materials which are currentlyknown, or later become known for performing the functions of theresealable portion or stopper described herein, such as any of numerousdifferent thermoplastic and/or elastomeric materials. In addition, thevials may be made of any of numerous different materials that arecurrently or later become known for forming vials, such as medicamentvials, including any of numerous different types of glass or plastic, orcombinations of glass and plastic. For example, the vial body can beformed of glass, and the base, locking ring and/or tamper-resistantcover can be formed of plastic, and can be joined to the body or to eachother in accordance with any of numerous different joining mechanismsthat are currently, or later become known, such as by over-molding,mechanical snap-fit or other interlocking engagements, by adhesivelyjoining glass to plastic, or by ultrasonically welding or otherwisewelding plastic to plastic. In addition, the needles used to fill thevials may take the form of any of the needles disclosed in Britishpatent application no. GB 0308705.2, filed Apr. 28, 2003, entitled“Novel Device,” the vial closure may take any of the forms of theclosures disclosed in British patent application no. GB0304268.6, filedFeb. 26, 2003, entitled “Novel Device,” the conveyor system and/or thecomponents thereof may take any of the forms as shown in British patentapplication no. GB0221510.1, filed Sep. 17, 2002, entitled “NovelDevice,” and the needle filling and/or processing stations may take anyof the forms shown in British patent application no. GB0221511.9, filedSep. 17, 2002, entitled “Novel Device,” each of which is herebyexpressly incorporated by reference in its entirety as part of thepresent disclosure. Accordingly, this detailed description of thepreferred embodiments is to be taken in an illustrative, as opposed to alimiting sense.

1-19. (canceled)
 20. A method, comprising: (a) penetrating an elasticseptum a device with an injection member, wherein the device defines asealed, empty sterile chamber in fluid communication with the elasticseptum, and the elastic septum defines a dome shape or a convex outersurface; (b) introducing a substance through the injection member andinto the sterile chamber of the device; (c) withdrawing the injectionmember from the elastic septum; (d) allowing the elastic septum toreseal itself at a penetration aperture resulting from withdrawal of theinjection member; and (e) maintaining the chamber sterile throughoutsteps (a) through (d).
 21. A method as defined in claim 20, wherein theelastic septum defines a substantially convex exterior surface, and asubstantially concave interior surface opposite the convex exteriorsurface.
 22. A method as defined in claim 21, wherein the elastic septumincludes a penetration zone defining an approximate dome shape, and thepenetrating step includes penetrating the elastic septum in thedome-shaped penetration zone.
 23. A method as defined in claim 22,wherein the approximately dome-shaped penetration zone defines asubstantially convex exterior surface and a substantially concaveinterior surface.
 24. A method as defined in claim 20, wherein theelastic septum is self-closing and substantially prevents the ingress offluid through the resulting penetration aperture.
 25. A method asdefined in claim 20, further comprising resealing the penetrationaperture of the elastic septum with respect to ambient atmosphere.
 26. Amethod as defined in claim 25, wherein the resealing step is performedby applying heat or energy to the elastic septum.
 27. A method asdefined in claim 25, wherein the elastic septum is compressed inwardlyin at least a penetration zone thereof to facilitate resealing of thepenetration aperture.
 28. A device that is sterile filled by aninjection member, wherein the device comprises: a body defining asealed, empty, sterile chamber; and an elastic septum defining a domeshape or a convex outer surface, wherein the elastic septum is in fluidcommunication with the sealed empty chamber and is penetrable by theinjection member to form a penetration aperture and permit substance tobe dispensed therethrough.
 29. A device as defined in claim 28, whereinthe elastic septum defines a substantially convex exterior surface, anda substantially concave interior surface opposite the convex exteriorsurface.
 30. A device as defined in claim 28, wherein the elastic septumincludes a penetration zone penetrable by the injection member anddefining an approximate dome shape.
 31. A device as defined in claim 30,wherein the approximately dome-shaped penetration zone defines asubstantially convex exterior surface and a substantially concaveinterior surface.
 32. A device as defined in claim 28, wherein theelastic septum is self-closing and substantially prevents the ingress offluid through the resulting penetration aperture.
 33. A device asdefined in claim 28, wherein the elastic septum is resealable or capableof being resealed at the penetration aperture to seal the chamber fromambient atmosphere.
 34. A device as defined in claim 33, wherein theresulting penetration aperture is resealable through application of heator energy to the elastic septum.
 35. A device as defined in claim 33,wherein the elastic septum is compressed inwardly in at least apenetration zone thereof to facilitate resealing the penetrationaperture.
 36. A device that is sterile filled by an injection member,wherein the device comprises: first means defining a sealed, empty,sterile chamber; and second means in fluid communication with thesealed, empty sterile chamber that is penetrable by the injection memberfor forming a penetration aperture and permitting substance to bedispensed therethrough, and for resealing itself at the penetrationaperture to substantially prevent the ingress of fluid through thepenetration aperture.
 37. A device as defined in claim 36, wherein thesecond means is an elastic septum that defines a dome shape or a convexouter surface.